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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE ) ) ) ) ) ) ) ) ) ) )

AFFYMETRIX, INC., a Delaware corporation, Plaintiff/Counter-Defendant, v. ILLUMINA, INC., a Delaware corporation, Defendant/Counter-Plaintiff.

Civil Action No.: 04-901 JJF

ILLUMINA'S REPLY IN SUPPORT OF ITS MOTION TO VACATE AS A MATTER OF LAW THE JURY'S VERDICT OF INFRINGEMENT OF THE `716 PATENT UNDER THE DOCTRINE OF EQUIVALENTS ON THE BASIS OF PROSECUTION HISTORY ESTOPPEL

Richard K. Herrmann (#405) MORRIS JAMES LLP 500 Delaware Avenue, Suite 1500 Wilmington, Delaware 19801 (302) 888-6800 [email protected] Robert G. Krupka, P.C. KIRKLAND & ELLIS LLP 777 South Figueroa Street Los Angeles, California 90017 (213) 680-8400 Mark A. Pals, P.C. Marcus E. Sernel KIRKLAND & ELLIS LLP 200 East Randolph Drive Chicago, Illinois 60601 (312) 861-2000

Dated: October 9, 2007

Attorneys for Illumina, Inc.

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TABLE OF CONTENTS Page No. I. THE FINDING OF EQUIVALENTS MUST BE VACATED ON THE BASIS OF AMENDMENT-BASED ESTOPPEL...........................................................................2 A. The Relevant Claim Limitation Was The Subject Of A Narrowing Amendment For A Reason Related To Patentability...............................................3 1. 2. B. II. The Element On Which Equivalents Was Found Was The Subject Of A Narrowing Amendment. .....................................................................3 The Amendment Narrowed The Limitation In Question For A Reason Related To Patentability..................................................................6

Affymetrix Cannot Rebut The Presumption Of Estoppel........................................9

THE FINDING OF EQUIVALENTS MUST ALSO BE VACATED ON THE BASIS OF ARGUMENT-BASED ESTOPPEL................................................................13

CONCLUSION..............................................................................................................................15

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TABLE OF AUTHORITIES Page No. Cases Ampex Corp. v. Eastman Kodak Co., 460 F.Supp.2d 563 (D.Del. 2006)..................................................................................... 10 Ampex Corp. v. Eastman Kodak Co., No. Civ.A. 04-1373-KAJ, 2006 WL 3359660 (D. Del. Nov. 20, 2006)......................... 5, 6 AquaTex Indus., Inc. v. Techniche Solutions, 419 F.3d 1374 (Fed. Cir. 2005)......................................................................................... 14 Bai v. L & L Wings, Inc., 160 F.3d 1350 (Fed. Cir. 1998)..................................................................................... 1, 10 Biagro W. Sales, Inc. v. Grow More, Inc., 423 F.3d 1296 (Fed. Cir. 2005)......................................................................................... 12 Cardiac Pacemakers, Inc. v. St. Jude Med., Inc., No. IP 96-1718-C-H/G, 2001 WL 912767, (S.D.Ind. June 14, 2001)................................ 5 Deering Precision Instruments, L.L.C. v. Vector Distrib. Sys., Inc., 347 F.3d 1314 (Fed. Cir. 2003)......................................................................................... 13 Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., Ltd., 344 F.3d 1359 (Fed. Cir. 2003)................................................................................. 2, 9, 10 Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., Ltd., 535 U.S. 722 (2002)............................................................................................................ 6 Freedman Seating Co. v. Am. Seating Co., 420 F.3d 1350 (Fed. Cir. 2005)........................................................................................... 5 Glaxo Wellcome, Inc. v. Impax Labs., Inc., 356 F.3d 1348 (Fed. Cir. 2004)......................................................................................... 10 Insituform Techs., Inc. v. CAT Contracting, Inc., 385 F.3d 1360 (Fed. Cir. 2004)......................................................................................... 12 Lockheed Martin Corp. v. Space Systems/Loral Inc., 249 F.3d 1314 (Fed. Cir. 2001)........................................................................................... 5 Lockwood v. Am. Airlines, Inc., 107 F.3d 1565 (Fed. Cir. 1997)..................................................................................... 7, 15

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Loral Fairchild Corp. v. Sony Corp., 181 F.3d 1313 (Fed. Cir. 1999)........................................................................................... 7 Network Commerce, Inc. v. Microsoft Corp., 422 F.3d 1353 (Fed. Cir. 2005)........................................................................................... 4 Read Corp. v. Portec, Inc., 970 F.2d 816 (Fed. Cir. 1992)........................................................................................... 14 Southwall Tech., Inc. v. Cardinal IG Co., 54 F.3d 1570 (Fed. Cir. 1995)........................................................................................... 14 Warner-Jenkinson Co. v. Hilton-Davis Chem. Co., 520 U.S. 17 (1997).............................................................................................................. 8 Rules 35 U.S.C. § 103...................................................................................................................... passim 35 U.S.C. § 112...................................................................................................................... passim

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Facing a textbook case of prosecution history estoppel on the `716 patent, Affymetrix's Opposition attempts to distract and confuse with various arguments that cannot be squared with the hard facts of the prosecution record for this patent. Affymetrix's after-the-fact advocacy cannot change the admissions that were made during prosecution of the `716 patent, or the evidence that was presented to support the doctrine of equivalents finding. The time for such calculated parsing of language was during prosecution of the patent, and by not doing it then Affymetrix must live with the consequences of its actions -- prosecution history estoppel barring application of the doctrine of equivalents on the limitation found to be met by equivalents by the jury. Affymetrix's arguments to escape estoppel run directly contrary to the governing case law and Affymetrix's positions during prosecution and at trial. For example: · Affymetrix now argues that the claim limitation in question was somehow not "amended," but this is contrary to its characterization in prosecution that "Applicants amended claim 60 to recite `each probe intensity indicat[es] an extent of hybridization...'"; Affymetrix now improperly tries to divorce the term "probe intensity" from "probe intensity indicating an extent of hybridization" to avoid the impact of its amendment, but this is contrary to Affymetrix's presentation of equivalents evidence on this limitation as a whole; Affymetrix now argues that the Examiner was only requesting "clarification" and "not suggesting that the scope of the claim encompassed unpatentable subject matter" (Affy. Opp. at 16), but this is directly contradicted by the fact that the claims were rejected under 35 U.S.C. § 112 and 35 U.S.C. § 103; Affymetrix argues that "Affymetrix certainly did not concede that it needed to amend the claim to overcome Weiss and Stockham" (Affy. Opp. at 19), but Federal Circuit case law states that a patent applicant "may not both make the amendment and then challenge its necessity in a subsequent infringement action on the allowed claim." Bai v. L & L Wings, Inc., 160 F.3d 1350, 1356 (Fed. Cir. 1998); and Affymetrix now argues the whole distinction of the `716 patent claims over Weiss and Stockham was on the basis that they did not disclose "arrays" (Affy. Opp. at 21, 24), but this ignores the fact that Affymetrix specifically argued at trial that asserted claims 1 and 5 of the `716 patent do not even require arrays. 1

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At bottom, Affymetrix spends twenty-eight pages trying to run away from the admissions it made during prosecution and at the phase one trial. But if Affymetrix wanted to argue that its amendment was unnecessary, or that the original claim language was just as broad as the amended language, it should have done so during prosecution. The Supreme Court and Federal Circuit have made very clear that the prosecution record itself must control the prosecution history estoppel analysis, and Affymetrix's belated efforts to draw fine distinctions that are found nowhere in the prosecution history must be rejected. See, e.g., Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., Ltd., 344 F.3d 1359, 1369 (Fed. Cir. 2003) (noting that the prosecution history estoppel analysis must focus on "the prosecution history record, if the public notice function of a patent and its prosecution history is to have significance."). The plain facts in the record mandate that the Court find both amendment-based and argument-based estoppel, and that the jury's verdict of equivalents be vacated as a matter of law on these independent grounds. I. THE FINDING OF EQUIVALENTS MUST BE VACATED ON THE BASIS OF AMENDMENT-BASED ESTOPPEL The Supreme Court and Federal Circuit have laid out a relatively straightforward set of guidelines to establish amendment-based estoppel. No matter how much rhetoric Affymetrix employs in its Opposition, the facts of this case fit within these guidelines. Affymetrix originally put forth a broader claim, amended the relevant limitation in response to § 103 and § 112 rejections, and then distinguished the cited prior art by pointing to the narrower claim language. The Festo presumption of estoppel is triggered by Affymetrix's narrowing amendment, and Affymetrix's attempt to argue that the "tangential" exception applies is without any merit.

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A.

The Relevant Claim Limitation Was The Subject Of A Narrowing Amendment For A Reason Related To Patentability.

The phrase "probe intensity indicating an extent of hybridization" was added to narrow the claims in response to multiple grounds of rejection by the Examiner. As discussed below, Affymetrix's various efforts to avoid this indisputable fact are unavailing. 1. The Element On Which Equivalents Was Found Was The Subject Of A Narrowing Amendment.

Affymetrix's first argument -- that the relevant limitation was not even amended -- flies in the face of the facts and law. Affymetrix's argument boils down to arguing that the term "probe intensity" is somehow a separate and distinct limitation from the limitation "probe intensity indicating an extent of hybridization...," and thus never amended. This new-fangled parsing of the claim by Affymetrix is directly contrary to Affymetrix's own prior admissions during prosecution and at trial, well-established case law, and a common sense reading of the claim. Contrary to Affymetrix's careful parsing of the claim language in its Opposition, Affymetrix presented proof of equivalents at the phase one trial on what it repeatedly deemed one claim limitation, not a series of mini-limitations within the first clause in the body of the claim. Affymetrix treated the following clause in claim 1 of the `716 patent as a single limitation at trial: ...computer code that receives a plurality of signals corresponding to probe intensities for a plurality of nucleic acid probes, each probe intensity indicating an extent of hybridization of a nucleic acid probe with at least one nucleic acid sequence including said sample sequence, and each nucleic acid probe differing from each other by at least a single base...

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(DTX 3 at IAFP179-180 (emphasis added)). For example, when pressed prior to trial as to how it would present its doctrine of equivalents case, Affymetrix specifically stated in its response to a motion in limine that it would offer evidence on the following single limitation: Affymetrix only intends to offer doctrine of equivalents evidence ... on the limitation "computer code that receives a plurality of signals corresponding to probe intensities for a plurality of nucleic acid probes, each probe intensity indicating an extent of hybridization of a nucleic acid probe with at least one nucleic acid sequence including said sample sequence, and each nucleic acid probe differing from each other by at least a single base." (D.I. 383, Affymetrix's Response To Illumina's Motion In Limine #2 (emphasis added)). Similarly, the doctrine of equivalents proof put on by Affymetrix at trial further belies Affymetrix's present effort to chop up the clause into multiple mini-limitations. The Federal Circuit requires "particularized testimony" and "linking argument" on a limitation-by-limitation basis to support a jury finding of doctrine of equivalents. See Network Commerce, Inc. v. Microsoft Corp., 422 F.3d 1353, 1363 (Fed. Cir. 2005). The proof put on by Affymetrix was not particularized to the term "probe intensity" separate and apart from the rest of this limitation; to the contrary, Affymetrix's expert only supplied one substantive answer per accused product with respect to the equivalence of this entire clause of the claim. Affymetrix's expert referred to the aforementioned limitation as a whole as "this claim element" or "this middle claim element." (See Trial Tr. (Guerra) at 809:14-810:17, 821:17-822:19). Likewise, the argument of

Affymetrix's counsel during closing also merely referred to this "middle element" without any of the parsing that Affymetrix is now engaged in. (See Trial Tr. (Affymetrix Closing) at 1615:231616:9, 1618:4-10). Affymetrix cannot be allowed to put on its "particularized" proof of

equivalents on the entire "middle element" during trial and then turn around and try to chop up this limitation into a series of sub-limitations when trying to avoid its prior amendment and thus estoppel. 4

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Indeed, several courts have ruled that such after-the-fact parsing of claim limitations is inappropriate, and cannot be used as a ploy to avoid prosecution history estoppel. See, e.g., Cardiac Pacemakers, Inc. v. St. Jude Med., Inc., No. IP 96-1718-C-H/G, 2001 WL 912767, at *3 (S.D.Ind. June 14, 2001) (rejecting argument by patentee to "to parse the claim language into affected portions and unaffected portions" to avoid the impact of an amendment); see also Lockheed Martin Corp. v. Space Systems/Loral Inc., 249 F.3d 1314, 1327 (Fed. Cir. 2001) (rejecting the parsing of a limitation to avoid estoppel).1 Even if Affymetrix did not run afoul of its own admissions before and at trial, and even if there was no case law denouncing such excessive parsing of claims, Affymetrix's argument that "probe intensity" is a completely separate limitation that was not amended during prosecution still makes no sense. The language that was added to avoid § 112 and § 103 rejections -"indicating an extent of hybridization of a nucleic acid probe with at least one nucleic acid sequence including said sample sequence" -- specifically defines what the probe intensity involves.2 The addition of claim language that modifies or defines existing claim language of course narrows the scope of the original language. See, e.g. Ampex Corp. v. Eastman Kodak Co., No. Civ.A. 04-1373-KAJ, 2006 WL 3359660, at *3 (D. Del. Nov. 20, 2006) (finding the addition of "said" to modify "data" narrowed the scope of this limitation). Thus, in addition to the

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Although the present standard establishes a rebuttable presumption of estoppel when a narrowing amendment is shown -- as compared to the irrebuttable presumption applied at the time in Cardiac Pacemakers and Lockheed (which was overruled by Festo) -- the logic behind the prohibition on parsing claim limitations to avoid an amendment and thus the presumption of estoppel applies equally under the current Festo standard. Moreover, if one were to read "probe intensity" separately from "indicating an extent of hybridization," and then allow the scope of equivalents to include "probe intensities" that do not indicate an extent of hybridization (like the equivalent found here), this would amount to an improper vitiation of the claim language and must be rejected. See, e.g., Freedman Seating Co. v. Am. Seating Co., 420 F.3d 1350, 1358 (Fed. Cir. 2005) (the doctrine of equivalents may not be used to entirely vitiate a claim limitation).

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various other legal impediments to Affymetrix's first argument, the argument simply does not comport with the language of the claim itself. No amount of claim language gymnastics from Affymetrix can separate the limitation for which equivalents was found from the amendment of that limitation during prosecution. The predicate for the Festo presumption of estoppel is therefore established. 2. The Amendment Narrowed The Limitation In Question For A Reason Related To Patentability.

Affymetrix next argues that there was no "narrowing amendment" to the claims because the amendment "was added pursuant to the examiner's request to clarify the meaning of the claim, rather than to avoid a prior art rejection." (Affy. Opp. at 15-16 (emphasis in original)). Once again, Affymetrix's argument is inconsistent with the governing case law and the prosecution record. Courts have routinely rejected arguments, like Affymetrix's here, that "clarifying" amendments cannot form the basis of amendment-based estoppel. Festo and its progeny have made very clear that amendments made to address § 112 indefiniteness rejections -- i.e. to "clarify" indefinite claim limitations -- do qualify as amendments that trigger a presumption of estoppel. See Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., Ltd., 535 U.S. 722, 737 (2002) ("On the other hand, if a § 112 amendment is necessary and narrows the patent's scope even if only for the purpose of better description - estoppel may apply. A patentee who narrows a claim as a condition for obtaining a patent disavows his claim to the broader subject matter, whether the amendment was made to avoid the prior art or to comply with § 112."); see also Ampex Corp., 2006 WL 3359660, at *3 (Jordan, J.) (rejecting same argument made by same counsel of record in this case, finding "contrary to Ampex's contentions, prosecution history

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estoppel does indeed apply to clarifying amendments" and an "amendment is no less narrowing simply because it was made in response to a § 112. But not only does Affymetrix's "clarification" argument fail on legal grounds, it also ignores the fact that the amendment was made in response to a prior art rejection as well. In addition to rejecting the original claims on the basis of indefiniteness under § 112, the Examiner specifically rejected all of the claims as obvious under § 103 based on Fodor in view of the Weiss or Stockham references. The amendment was therefore made, at least in part, to

distinguish the cited prior art.3 And Affymetrix's prosecution conduct after amending the claim to add the language in question further confirms that amendment was narrowing in nature. In distinguishing the Weiss and Stockham references, Affymetrix repeatedly referred to the newlyadded language -- not just the original language -- to overcome the § 103 rejection. The reliance on the language added by amendment -- by both Affymetrix and then the Examiner in allowing the claims -- confirms that this amendment narrowed the claims for a reason related to patentability. See, e.g., Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1575 (Fed. Cir. 1997) (reliance on language added by amendment to overcome a prior art rejection established estoppel). Finally, with respect to Affymetrix's argument that the overall claim did not change in scope as a result of the amendment, this is also contradicted by review of the prosecution record. Affymetrix tries to point to language from another part of the original claim that required that

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Although it does not really matter to the present analysis given Festo's clarification that an amendment in response to a § 112 rejection is enough, courts have previously criticized litigants for the ploy that Affymetrix seeks to put forth here. The Federal Circuit has cautioned that "[a]n applicant may not avoid the conclusion that an amendment was made in response to prior art by discussing the amendment under the rubric of a clarification due to a § 112 indefiniteness rejection." See Loral Fairchild Corp. v. Sony Corp., 181 F.3d 1313, 1326 (Fed. Cir. 1999).

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probe intensities be "substantially proportional to a probe hybridizing to at least one sequence" and implies that the overall scope of the amended claim did not change.4 Even if one attempts to follow Affymetrix's strained argument, it still falls short because a requirement that the probe intensity indicate an extent of hybridization is unquestionably narrower than language that merely requires that the intensity be substantially proportional to a probe hybridizing with a sample. Indeed, the amended language makes all the difference in the world when considering the infringement question that was presented at trial -- the claims were not literally infringed because they required that the probe intensity indicate the extent of hybridization (since Illumina's assays used enzymes to generate the intensities) -- whereas Affymetrix may have been able to prove literal infringement if the claims allowed for the probe intensity to merely require substantial proportionality to a probe hybridizing with a sequence. The change from merely requiring some relationship ("substantial proportionality") to requiring a more specific relationship ("indicating the extent of hybridization") is critical when considering that Illumina's intensities were generated from enzymatic-based assays that manipulated up-stream hybridization reactions. Thus, even if Affymetrix's "overall scope" argument is legally viable, it factually falls short as well. Affymetrix's arguments therefore fail for a number of reasons, the relevant limitation was narrowed by amendment for patentability reasons, and the presumption of estoppel applies.

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Equivalence is of course judged on a limitation-by-limitation basis, and not from the perspective of the invention as a whole. See, e.g., Warner-Jenkinson Co. v. Hilton-Davis Chem. Co., 520 U.S. 17, 29 (1997).

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B.

Affymetrix Cannot Rebut The Presumption Of Estoppel.

Although Festo established three possible exceptions to rebut the presumption of estoppel, Affymetrix concedes in its Opposition that two of these three exceptions are inapplicable. Instead, Affymetrix solely relies on an argument that the amendment of the limitation in question was tangential to the adjudicated equivalent, but this requires a complete distortion of what the "tangential" exception was established to address. The tangential exception to the Festo presumption of estoppel can preserve a finding of equivalence where an amendment has no real relation to the equivalent in question. Festo Corp., 344 F.3d at 1368. No matter how much Affymetrix may want this exception to save the equivalents verdict, it simply has no application to the facts of this case. Affymetrix's

amendment during prosecution in response to the § 112 and § 103 rejections was made at least in part to avoid prior art (including Weiss and Stockham), and then the new language in turn was used to distinguish this prior art by pointing to the newly narrowed claim limitation. There is no dispute that the Illumina products adjudged to be equivalent use enzymes and tags to generate enhanced intensities. (See, e.g., Trial Tr. (Quackenbush) at 1226:18-21, Trial Tr. (Guerra) at 873:10-13, 874:7-11). The prosecution record reveals that Weiss taught a similar approach, as described by Affymetrix itself in response to the Examiner's §103 rejection: ...Weiss describes utilizing an enzyme on identical probes that hybridize with tags in the fragments of the nucleic acid ladder. The enzymes convert a fluorogenic substrate (e.g., BBTP) into a fluorescent product in order to enhance the pattern of hybridization.... (DTX 4 at IAFP402) (emphasis added)). After noting that the prior art Weiss and Stockham references employed enzymes to generate enhanced intensities in their methods, Affymetrix stated:

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In stark contrast, the present invention compares probe intensities that indicate the extent of hybridization of probes differing by a single base and the sample nucleic acid sequence. (DTX 4 at IAFP403 (emphasis added)). The Examiner then specifically relied on the distinction that was drawn by Affymetrix, noting that "[t]he closest prior art of record is Weiss and Stockham" but that these prior art references did not teach the amended language of "...probe intensities indicat[ing] an extent of hybridization of probes differing by a single base..." (DTX 4 at IAFP414). The cold prosecution record speaks loud and clear -- the amendment was made to avoid prior art (that disclosed the use of enzymes to enhance hybridization intensities) and was central to the allowance of the claims. This is the antithesis of a tangential amendment. "[A]n amendment made to avoid prior art that contains the equivalent in question is not tangential; it is central to allowance of the claim."5 Festo Corp., 344 F.3d at 1369 (emphasis added). It is indisputable that (1) Affymetrix made its amendment (at least in part) to avoid the Weiss and Stockham prior art6, and (2) Weiss and Stockham contain the equivalent in question (intensities enhanced by the use of enzymes). There is no need to go further in the analysis -- the amendment cannot possibly qualify as tangential. The pages upon pages that Affymetrix spends distorting and distinguishing the Weiss

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Affymetrix states "that the prosecution history contains no indication that the claim was amended to overcome the prior art." (Affy. Opp. at 21 n.3) Affymetrix's statements are simply incorrect as issued claims 1 and 5 of the `716 patent contain the same amended language first present in amended claim 60, which was amended to overcome a § 103 prior art rejection. (DTX 4 at IAFP390, 399, 402-403). See Ampex Corp. v. Eastman Kodak Co., 460 F.Supp.2d 563, 568 (D.Del. 2006) ("Any subject matter surrendered via claim amendments during prosecution is also relinquished for other claims containing the same limitation.") (quoting Glaxo Wellcome, Inc. v. Impax Labs., Inc., 356 F.3d 1348, 1356 (Fed. Cir. 2004). As mentioned above, a patent applicant cannot amend claims in the face of a prior art rejection and then argue later that the amendment was not needed to avoid the prior art. See, e.g., Bai, 160 F.3d at 1356.

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and Stockham prior art references have no bearing on the presumption of estoppel or Affymetrix's inability to rebut it.7 Even if Affymetrix's new arguments to distinguish Weiss and Stockham are considered, however, they are inconsistent with the prosecution record and Affymetrix's own prior statements in this case. Affymetrix now argues that the entire focus of the prosecution

arguments was to distinguish the "sequencing ladders"8 of Weiss and Stockham from the "arrays" of the `716 patent. (Affy. Opp. at 21, 24). Affymetrix cannot cite, however, to a single statement in the prosecution record that draws a distinction on the basis of this "arrays" argument. Indeed, there is no such evidence in the prosecution record. And this is not

surprising, as Affymetrix itself when arguing about the scope of the claims in this case has specifically noted that asserted claims 1 and 5 of the `716 patent do not even require the use of arrays. (See, e.g., Markman Hearing Tr. at 60 (when describing claims 1 and 5 of the `716 patent, Affymetrix's counsel argued "the probes don't need to be an array"); Trial Tr. (Affymetrix Closing) at 1622:9-12 ("What that shows that you don't always have to be in an array of probes. The other claims [i.e. 1 and 5] cover where there aren't [an] array of probes.")). Thus, Affymetrix's new argument that the claims were distinguished on the basis that they

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Affymetrix's arguments to identify differences between Weiss and Stockham and the `716 patent claims are misguided because, inter alia, they completely ignore the fact that Weiss and Stockham were cited as part of § 103 obviousness combinations. To the extent that Affymetrix is even correct about some of the distinctions it attempts to draw with the Weiss and Stockham references -- and many are in fact gross distortions -- the reality is that these trivial differences are in fact taught by the Fodor reference that was cited in combination with Weiss and Stockham, so they are really irrelevant to the patentability of the claims as discussed during prosecution. Affymetrix's use of the term "sequencing ladders" to describe the prior art cannot obscure the fact that these references disclose enzymatic-enhanced intensities from hybridization reactions, and these intensities are then used to make base calls (i.e. determine sequence), very similar to the enzymatic-based assays used in Illumina's products.

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required the use of "arrays" is completely inconsistent with their prior arguments that these claims do not even require arrays. The cases Affymetrix cites also are of no moment. For example, Affymetrix's reliance on Insituform Technologies, Inc. presupposes that there is no relationship between the narrowing amendment and the alleged equivalent -- this is simply not the case here. See, e.g., Insituform Techs., Inc. v. CAT Contracting, Inc., 385 F.3d 1360, 1370 (Fed. Cir. 2004) ("There is no indication in the prosecution history of any relationship between the narrowing amendment and a multiple cup process, which is the alleged equivalent in this case.") Where Affymetrix

specifically noted that the prior art disclosed enzymatic-generated intensities, and at the same time amended its claims and expressly argued with respect to patentability due to the limitation directly tying probe intensities to the "extent of hybridization" (as opposed to the extent of enzymatic reaction or something else), Affymetrix's rationale underlying the amendment is anything but tangential.9 Biagro W. Sales, Inc. v. Grow More, Inc., 423 F.3d 1296, 1306 (Fed. Cir. 2005) (holding patentee "cannot claim that the rationale for the amendment is merely tangential" when the reason for the amendment and the accused equivalent in the case both relate to the concentration of the fertilizer) (emphasis added). Affymetrix's amendment of the claim limitation in question was anything but tangential to the adjudged equivalent, and thus Affymetrix cannot overcome the presumption of estoppel. The finding of infringement under the doctrine of equivalents must be vacated on the basis of amendment-based prosecution history estoppel.
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In what may be its most desperate argument, Affymetrix states that it "no more distinguished the use of `enzymes' or `tags' than it did `DNA.'" (Affy. Opp. at 22). The difference, of course, is that Affymetrix did expressly distinguish the prior art on the basis that they employed enzymes and tags, but never mentioned DNA as a point of distinction (because it is not).

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II.

THE FINDING OF EQUIVALENTS MUST ALSO BE VACATED ON THE BASIS OF ARGUMENT-BASED ESTOPPEL In addition to establishing amendment-based estoppel, Affymetrix's arguments during

prosecution also form the basis to find argument-based estoppel as well.

The analysis of

argument-based estoppel has a somewhat different focus than amendment-based estoppel; because there is no presumption of surrender based on a narrowing amendment, the analysis centers on what was "clearly and unmistakably" surrendered by the statements made during prosecution. Deering Precision Instruments, L.L.C. v. Vector Distrib. Sys., Inc., 347 F.3d 1314, 1326 (Fed. Cir. 2003). Thus, while many of Affymetrix's arguments regarding the prior art and what was specifically said during prosecution are largely irrelevant to the amendment-based estoppel analysis, these arguments are at least potentially germane to the argument-based estoppel analysis. In any event, the prosecution record still reveals that Affymetrix clearly and unmistakably surrendered the enzymatic-type assays that were found equivalent by the phase one jury, and a finding of argument-based estoppel is thus warranted as well. Affymetrix surrendered the alleged equivalent -- use of enzymes and/or tags for labeling and detection -- through its distinction of the Weiss and Stockham prior art references during prosecution. Affymetrix specifically called out the presence of enzymes and tags in these prior art references, and specifically noted the impact of enzymes on the intensities from hybridization reactions. Affymetrix was then very clear in drawing the distinction between the enzymaticenhanced intensities of the prior art and the intensities generated by the invention of the `716 patent, stating that "[i]n stark contrast, the present invention compares probe intensities that indicate the extent of hybridization of probes differing by a single base and the sample nucleic acid sequence." (DTX 4 at IAFP403) (emphasis added). While Affymetrix now tries to distract attention to the arguments in prosecution relating to fluorescent signals and other differences in 13

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the prior art, these arguments merely flow from the fact that the prior art used enzymatic-based assays and the `716 patent claims did not. The cases cited by Affymetrix do not undermine a finding of argument-based estoppel. Affymetrix fails to point out that in AquaTex "[t]here [was]...no indication in the prosecution history whether or not AquaTex agreed or disagreed with the examiner's statement that the fiberfill found in the prior art comprised natural fibers." AquaTex Indus., Inc. v. Techniche Solutions, 419 F.3d 1374, 1383 (Fed. Cir. 2005). In this case, however, Affymetrix squarely addressed the § 103 rejection by the Examiner, and in conjunction with its amendment clearly and unmistakably called out the alleged equivalent while distinguishing the claim limitation from Weiss and Stockham. (Ill. Br. at 17-18; DTX 4 at IAFP402-403) More particularly, Affymetrix expressly noted the use of enzymes, and their impact on the signal or intensity, in drawing distinctions over the prior art. Although Affymetrix may have described other aspects of the Weiss and Stockham references as well, these "other distinctions" do not avoid the fact that use of enzymes to enhance intensities was relinquished. See, e.g., Southwall Tech., Inc. v. Cardinal IG Co., 54 F.3d 1570, 1582-83 (Fed. Cir. 1995) (criticizing the interpretation of Read Corp. v. Portec, Inc., 970 F.2d 816 (Fed. Cir. 1992) put forth by Affymetrix here (see Affy. Opp. at 25), explaining that "Read does not hold ... that arguments made during prosecution can only create an estoppel regarding the combined distinctions and can never create separate estoppels.... For instance, any argument made regarding the need to distinguish the prior art ... does create a separate estoppel, regardless of other distinctions made."). Affymetrix cannot be allowed to distinguish Weiss and Stockham during prosecution on the basis of their use of enzymes and/or tags, and then switch course and argue that they only distinguished certain uses of enzymes and tags when trying to evade a finding of estoppel.

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Contrary to the picture that Affymetrix seeks to paint in its brief, the enzymes in the Weiss and Stockham references perform the same basic function as those used in the Illumina products adjudged to infringe -- enhancing (i.e. sharpening) the intensity from a hybridization reaction. In any event, Affymetrix certainly did not compare and contrast different forms of enzymes or tags when distinguishing the prior art during prosecution. Affymetrix cannot introduce a new extrafine level of distinction for the first time in its briefing on prosecution history estoppel; Affymetrix's more general arguments during prosecution must govern the analysis. See, e.g., Lockwood, 107 F.3d at 1575 (rejecting patentee's attempt to avoid estoppel by drawing a finer distinction between alpha-numeric displays and graphical displays where such a distinction was not drawn during prosecution). Since Illumina's products that were found to infringe under the doctrine of equivalents employ the use of enzymes and/or tags for labeling and detection, the principles of argumentbased estoppel also dictate that the finding of equivalents be vacated. CONCLUSION For the foregoing reasons, Illumina respectfully requests that this Court grant its Motion to Vacate the Jury's Verdict of Infringement of the `716 Patent as a Matter of Law and find that Affymetrix is estopped from asserting the Doctrine of Equivalents.

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Dated: October 9, 2007 /s/ Richard K. Herrmann Richard K. Herrmann (#405) MORRIS JAMES LLP 500 Delaware Avenue, Suite 1500 Wilmington, Delaware 19899-2306 (302) 888-6800 [email protected] Robert G. Krupka, P.C. KIRKLAND & ELLIS LLP 777 South Figueroa Street Los Angeles, California 90017 (213) 680-8400 Mark A. Pals, P.C. Marcus E. Sernel KIRKLAND & ELLIS LLP 200 East Randolph Drive Chicago, Illinois 60601 (312) 861-2000 Attorneys for Illumina, Inc. _

16

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EXCERPTS FROM DTX 3

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'

United States Patent
Chee et a. l

t9 11

[ I ~ IPatent
[43

Number: Date of Patent:
a992

57576 ,9,1
Aug. 18, 1998

1541 C O ~ ~ ~ E F I - A I DYISUAIlWLTION A M ) ED ANALYSIS SYSrW FOR SEQUENCE

rY0 9Y105M

WIPO .

EVALUATION

9 I l 9 Y1995 WIPD. 5J95 W O ~ ~ ~ S S WIPO.

p&l

lnvcntcux

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M o , C 6 943CKk Robert 1Lipsboh aC ¶O W o Aim Ave- Palo Alto. C l aX

UlW3 PUBLICMXONS

94381 I 1 AppL No.: 327525 21

Drmanac d a 1 DNA m Kkfumbtio. by hybrid& a t i o M shacgy for Effck5m Lage Scalc Squcadng Scicacr 28): 1649-1652 1 9 . 93 Sbooska a rL DNA scqusaing by Ilytdklion :100
basudbya~bilSCdlDCtbDdPNASI:

~oo~p-~m.i~~. Drnmnac d aL h algaittun fur the DNA Scqucocz Gcncralion faun k-Tuple W d ContcoU d a Minimal Nu& b a ofRandom Fragmcnu. L of BiShucfmc & DyDmnicr % 1065-llm. 1 9 . 91 .SollIhum a d Aaalyrimg and Chmpiog Nuddc Add Sequences by Hybrimon UI Amys of Oligonudcotidcr. EYahlafion using E3puimmtlls Mod& -omin 1: 3 1WS-1017.1992

-

US. P

m DOCLTMENIS

4.141.043 # 9 1 Bra. I8 4.965.725 1M993 aL 5.KQ36) 3tI991 M6a 5 W 2 3 1 4n993 Drmmr ad.. 5273.632 12/1993 Swd3-n d A. 5 m z 6 1 1099s WWP u d . 5.445934 M99s ? a & J . 5 4 0 7 0 1 1 9 5 Wek a d. .7.1 119 . 5.492.806 ~1996 - a . h L 5Z,6 S S 4 4 Ql996 a st . 5 J n . a l 6n996 Holma

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- - -

A wmpum ryscm far analyzhg n d d c acid suplcom is Tbz wmpula syslcm is uccd 10 pfmn multipk mclhodrfa dumnining uchcwn basu by analyzing L c 43516 fluonscracc inlcnsirier oT bybddizd Ducldc arid prober The rcmk of individual qaiinmn arc iuqmvcd by pr0GcSsiD.g nuddc acid equc~rrrmgdher. Compatjvc 43~18 ~ysisdmuhiplo~ObnLaprovidul& by 435% plrying r d a c n a scqucnces in one z a u and urnplc scqucnm in &aca w a dirplay dmM4356

pro-

-

43%

1

Affymetrix v. Illumina C.A. NO 04-901 JFF Trial Exhibit

DTX3

1

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I i i)
1. i

~lT+2mcIpeLdt)
T

)oqOa9-.m~)IDn:

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Ix i) = I D CTOOOCOGTA

5

Wlutisdaimcdisr 1. A mmpllcr P O Ipodud rhat idcutdies an LUX in a sample nuddc add wgucma, mmp;rir
ing:

--~codtmlrr-aapledti@amespoodioa to mk irdrasitia for o l

a ~ d P o b c J . ~ m F o a ~ ~ ~ ~ B a ~ dC qX g~ ~ a f f a~ d n u d e i c a d d p o k r ; ~ d n d p . o s i a m p u rudrblc mdimn lbal ntrcs uid mmpl~cr mur hytnihtiw d 8 DUC& add probe rpim-atkar( wc
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~ ~ ~ ~ ~ c e m d j n g ( o r a u l ~ d w i d ~ ~

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5,795,716
43
44
d a r S
1 mmp10 r d b mtdbm ooufid Io a i d pomwa uak A computa program produd char idenrihcs an m b a s e H ~ s a m p k ~ c x j d a q o c s l a . m ~ fcr&g~~lbpogrammmpdsing: ~ r o d c ~ ~ a 1 ~ d

~ b r r e ~ g , o . b . a d * m d d ~ d m e n a d said supvam of said nucldc a d d p r ~ b . v i . g w i d h t g b u p m b c i m c p r i r O i f u i d ~ ~ i r ~ pub. g f ~ ~ ~ . 8 a n a p ~ & v a I n c ; L d 6.~syspmIMidcoliSa??ualraoambu+ioa~ a C o g l P M ~ b k J m f i u I n ~ n m c t p l i d a D I s p u r a nu*.ddaqa: coQ 1proepw;d 3. A oompwa propm podr u i d c a f i s aa h rn ~JT@~CIBIW mcdinm coupled 10said pm=xr lbpotvn base w a sample nuchie acid scqcena. w + l swing a wopma f r y wrpkiug: a mmpua a tba~I ~ C aS @raliq d signab & S compulcrcMchI~vna6rs(se(of~a~~~c ~ ~ g t o p o b c i s ~ u f ~ ~ spondiog w lun set o pobe indf cach pmbc nud& add pobtr. rub p b =btcmity b d k h g i* n io G d wl b d h l i n g an uhtdbybridw mlcm cb hybidizstioa d a mdcic acid pobe izalion of a nuddc add probe with r rrlcma nuckic witb said saz+ vqumcr md och nlrkic acid pobc diffaingfromud~&ubyatlenasiDglc acid scquerrrr a d c d mddc nciU probe ditlaiq a fmm cad, or&r by a l s r l a single hw. hw; a d o of c o w - mde c o m p t u ccdc &XI &vcr a s o o n d sa o signals f imcasiry TO a Iowa p b e HrcDdty. and ~~g to a xeoDd s d d p ~ h ~ ~ ~ ~ i t~i a . C X ~ L r cDde thr g c l l m a brrc 011 i b f y i o g r probe os in ci ty in said s ~ n sd indicating . u m X , d n tt s i r m b o m bnst accordiag to a baa of r rmclcic ad of hybddizltian d a n u d e r i d pmbc w i U ~ said acidprdxbavhgsnidhigbr+pbciu~ifsaid snmplc wpleofe. m ucb n n d a c 2% probe dilfaia~ d 1 ratio is gmala &an a prrdclamiosd ntio vrrlur f m m e Q b a b y a t I d a singkbm; c a n p t ~ ~ ~ t i t a ~ ~ ~ ~ m f s c o m p l d s w o f a t l .~ A o c y z l c m ~ * t i f i ~ U ' ~ o ~ ~ b a ~ C 7 o S 'c o said probe in(tosi6itia in said 6m and u lcau ollt35 ~ u ~ Pad* ICIJUCDO. f apaesr0r;Pd of uid ptk i~lcasilio said s Q ~ SCI; ~ d a c n m ~ ~ t m b l c mcdium rouplcd to said poccrsor ml mmpmcr code a a baseall i w b g ~ ~ w n b a r c a ~ g ) o r c d ~ o f s a i d c X ~ ss l a i n g a m m p u c c r ~ ~ ~ u compnaca* h1fuxivur6xts4 ofafgnakarc said sequence d said mdcic &id wok; and rcspoudbg 10Frobe i u l tu crcb pok iwmily L as i . S canpltcr mbbk mcdium h sll said complnrr > . in sSd fr % i s in&m.tincar, aid ob hvhidizrliw I d a nuddc acid pmbc Gilb a rdLuddcacid 4. A computa program 'podud idwlifics an q r m a . md mcb nudde rddpmbeMaingfrom unknown base in a ample nuJcir add s q u c n a . comprir each ocher by at l a s t a siagle bar i ar -r CoWUW C d C h -Q l *& CxrrCsp~diog10 saaIiaics ahow a plivality d - . l r c a d of &d nptrimenu podu&g pobc od pobc ioltady indiemkg u atcol of hyhi&mtip. of a nudcic acid poh: with a ~ C M R npclac add nqucluc. md a l nudcic acid pmh di6ning Irom 5a d c~olhubya(1~aSklgkbuc: D o m p u v r m d c m M i v a .pL\8LiryofsigoaL mrr*

-

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" indicating an u u a t d h 0 " ~ d Fobc Whb said sample s t a r 5 nudecadd embcdiKaingfromcrderbabyukact.Si.glcb.55 c o m p l ~ ~ ~ ~ p a f o Ofsaid $mrlity o f p r o k i e t a u i t k ~ wifh uid S a m .

spmding lo pobe i n ~ - t i e r .c c probe h c d y .b cp r

' corqprirr ~ ~ g. ea t s c tx.~ ig w d tubown basc vmdimg l o rrsllhr of s l d m@on d wid scqucua of nuddc acid p b ~ bAysaemtbai&,~i6er~ohownbswiorsrmplc ~ ~ r * ~ ~ e n& acid M c o m p u l n ~ l h a ~ c m a a a b w c d l i d r a ~ g s a i rpoce+IQ:ad d~ unknown bsrc acwrding mrcsuUI d d mmpmisn a m k mvpkd I d D and said 3cgucna o said D & f U d d rod IastabgaanrqnI~FIPiM~ r complt~ b b l c medium tha~ a c s said c o m p ~ m s corqum eDdc hat rsc*a signals famqandi~gt o

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EXCERPTS FROM DTX 4

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rrc+ardcnrr i s k i n g I dFreb, certlfy chat r: h smr bj facsimile t r S S i s r l o n to: Examiner D. Ices. Ph.D-

FBI Yo. : 1-703-305-7LOl

PATENT

Attorney Docket No. 16528X-0?8200 (client file no. 1091)

IN TRE DNfTED STATES PATENT AND TRADEMARK OFFICE

In re application of; HARKS. CHEE ET.AL.

1
Arttlnit: 1807

Application No. :

08/327,525

Filed: October 21, 1994

)

or:

COMPUTER-AIDED

1
)

VISUALIZATION AND ~ A L Y S ) IS SYSTEH FOR SEQUENCE EVALUATION

AMENDNENT

Assistant commissioner for Patents Washington, D. C . 20231
Sir:

In'response to the Office Action mailed December 19,
1995, f o r which a petition for an extension of time is enclosed,

please am&d this application as follows.

RJ PHE CLAIMS: .Please cancel claims 4-3-2dand 4 5 - 4 without prejudice. Please add new claims 60-105 as follows.

'

-_ -.

1-59. - - C A W F Z D - C

system, a method of identifying an

other by a single

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naRR 5 . CHEE ET aLA p p l i ~ t i o nO : N. 08/327,525 Page 10

PATENT

a ) I n regard t o claim 1, the Examiner s t a t e d t h a t it i s not c l e a r how a probe i n t e n s i t y i s associated with a nucleio acid probe. A s t h e ~xaminersuggested, Applicants amended claim 60 t o r e c i t e "each probe i n t e n s i t y indioatces] an extent of hybridization of a nucleic acid probe with at l e a s t one nucleic acid sequence including s a i d sample sequence." Accordingly, t h e rejection does n o t apply t o t h e new c l a h s . b,c) Also Sn regard t o claim 1, t h e &aminer s t a t e d t h a t "substantially" and nassociated" were i n d e f i n i t e o r lack antecedent b a s i s - A s claim 60 does not contain these words, t h e rejection does n o t apply t o the new claims. d) I n regard t o claim 1, the Examiner s t a t e d t h a t it i s unclear hov "calling" is defined. Claim 60 r e c i t e s ihstead "identifying s a i d mknown basem a s was suggested l y the Eximiner a h paragraph e . !!e Examiner a l s o s t a t e d t h a t t h e r e seems t o a ) !h s t e p missing. Applicants do not believk t h a t any s t e p s a=e missing i n claim 60. Accordingly, t h e r e j e c t i o n does not apply to t h e new claims. , e I n regard to claim 4 , t h e Examiner s t a t e d that t h e l phrase l l c a l l i n g s a i d unknown base a s being a base" is unclear. Claim 60 r e c i t e s instead lridentifying s a i d unknown base" as suggested by t h e Examiner. Additionally, the Examiner s t a t e d that it is unclear what a "predetermined r a t i o value" is. A predetermined r a t i o value is typically a constant number l i k e 1 - 2 (see, e-.g.'. claim 63). definiteI n the intemiew, i t is believed t h a t t h e
Examiner k t a t i v e l y ' agreed t h a t this G h r a s e is patentably

f] I n regard t o claim 6, the miminer stated that the "Step of sorting1' i miclear- Claim 64 recites that a s t e p of s s o r t i n g probe i h t e n s i t i e s is done "before said comparing stept1 (see, e-g. , page 1 4 , l i n e s 17-22 3 . ~ c c o r d i n g i y , the r e j e c t i o n does not apply t o t h e nev claims. g) In regard t n claim 9 , the Examiner s t a t e d that it is unclear how "wild-typew is defined uith respect t o the "reference sequence." Claim 67 r e c i t e s t h a t the wild-type probe intehsity indicates t h e extent of hybfidieation of a complementary grobd w i t h the reference sequence. . Since t h e reference s v e n c e is a

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MAY 20 '96

0 : 3 P TTC PFlLO RLTO 415 326 2422 45Pl

~.28/24

MARK S - CEIEE ET A -

PATENT

Application No.: Page 13

081327,525

( i d e n t i f y i n g ) methods of t h e p r e s e n t invention. For t h e f o l l o v i n g reasons, t h e s e r e f e r e n c e s do n o t d i s c l o s e o r suggest
the p r e s e n t invention

ad claimed.

Weigs and Stockham a r e r e l a t e d t o n u c l e i c a c i d

sequencing which u t i l i z e s n u c l e i c a c i d ' l a d d e r s which may b e formed by w e l l known techniques such a s t h e Sanger dideoxy method o r the M a x a m and c i l b e r t method- More & p e c i f i c a l l y , Weiss describes u t i l i z h g an enzyme on i d e n t i c a l probes t h a t h i b r i d i z e The w i d t a g s i.k t h e fragments o f . t h e n u c l e i c a c i d l a d d e r . enzymes convert a fluorogenic s u b s t r a t e ( e - g . , BBTP] i n t o a f l u o r e s c e n t product in o r d e r t o enhance t h e p a t & r n of h y b r i d i z a t i o n (see, e-g., Fig. 1 2 . ') Stockham, more s p e c i f i c a l l y , d e s c r i b e s methods of sharpening s i g n a l peaks from e l e c t r o p h o r e t i c m i g r a t i o n p a t t e r n s of n u c l e i c a c i d laddersEach fragment of t h e n u c l e i c acid ladder i s l a b e l e d with a r a d i o a c t i v e label which is u t i l i z e d t o i d e n t i f y t h e p o s i t i o n of t h e fragment on t h e g e l following e l e c t r o p h o r e s i s . As analyzing t h e mig$ation p a t t e r n s is time consuming and o f t e n error prone, Stockham d e s c r i b e s equations and formulas for increasing.the accuracy o f . t h i s p r o c e s s (e-g-, sharpening s i g n a l peaks) ' ~ e i s s n d Stockham do n o t d i s c l o s e o r s u g g e s t &utting a probe i n t e n s i t i e s t o i d e n t i f y an unknown b a s e where t h e probe i n t e n s i t i e s i n d i c a t e t h e e x t e n t of h y b r i d i z a t i o n of probes d i f f e r i n g by a single base and the sample n u c l e i c a c i d sequence. claim 60 r e c i t e s the following: in~utt'n a ra ' t of robe i n t e 'ties for:a plurdity o n t e n s a t y i n d i c a t h u an extent of h v b r i d i z a t i o n of a nucleic a c i d probe v h at l e a s t one n u c l e i c a c i d sequence including i s a i d sample sequence, and each n u c l e i c acid probe d i f f e r i n s from each other bv a sinule base; (emphasis s u p p l i e d ) - Neither Weiss n o r Stackham discloses t h e s e limitations. I n i t i a l l y , Reiss uses a s i n g l e probe which w i l l hybridize t o a t a g on t h e n u c l e i c a c i d l a d d e r fragments.
As

such, a l l of the "probes" in Weiss a r e identical.

Fnrthermore,

t h e probes i n W e i s s do n o t indic?ate.the e x t e n t of h y b r i d i z a t i o n b u t i n s t e a d are u t i l i z e d t o generate a f l u o r e s c e n t signal which

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.

.

.. .

llRY 20 #96 04:53PH TTC p i 0 RLTO 415 325 2.422

P.ZiR4

MARK 5 . CHEE EP rrL. Application No.: 0 8 / 3 2 7 , 5 2 5 Page 1 4

i n d i c a t e s t h e location of a fragment on t h e s u b s t r a t e . Accordingly. it i s t h e l o c a t i o n of t h e fragments t h a t i s u t i l i z e d t o sequence a n u c l e i c acidStockham does n o t u t i l i z e probes a t a l l . Instead. stockham r e c i t e s that t h e fragments of t h e nucleic a c i d ladder a r e r a d i o a c t i v e l y labeled. The r a d i o a c t i v e s i g n a l r e s u l t i n g i n d i c a t e s the p o s i t i o n of the fragments on the g e l ih a w a y which is s i m i l a r t o ~ e i s s . Accordingly, Stockham a l s o u t i l i z e s t h e location of the fragments t o sequence a nucleic acid. I n stark contrast. t h e present invention compares probe i n t e n s i t i e s that i n d i c a t e t h e extent of hybridization of probes d i f f e r i n g by a s i n g l e base and t h e sample nucleic a c i d sequence. Claim 60 recites the following: s a i d computer system comparing s a i d p l u r a l i t y of probe i n t e n s i t i e s ; and i d e n t i f y i n g s a i d unknown base according t o results of s a i d comparing step. I n t h e Office Action, t h e Examiner s t a t e d t h a t it would have been prima f a c i e obvious t o one of o r d i m a r y ' s k i l l i n t h e a r t t o , u s e the computer algorithms of Weiss and Stockham t o i n t e r p r e t ' t h a t data from the sequencing by hybridization described by FodorMare s p e c i f i c a l l y , t h e Examiner s t a t e d t h a t one could "call" a s i t e based on the i n t e n s i t y of a s i g n a l produced by a probe a t that s i t e ' a n d t h u s as.sign an i d e n t i t y t o t h a t s i t e . Applic.ants disagree. ' .Weiss and Stockham r e l a t e t o v a s t l y different technologies than the pioneering advances of Fodor. W e i s s and Stockham a r e d i r e c t e d . t o i d e n t i f y i n g t h e l o c a t i o ~ a fragment of Ln t h e presenk invention, t h e . of a nucleie a c i d ladder. locations of the hybriclized probes are known and, a s such, the computer algorithms of Weiss and Stockham would indeed seem t o teach away from the present invention which is d i r e c t e d t o c a l l i n g an unknown base according t o probe i n t e n s i t i e s from nucleic a c i d probes t h a t d i f f e r by a s i n g l e baseA s W e i s s and Stockham do n o t d i s c l o s e o r suggest a l l t h e l i m i t a t i o n s of claim 60. t h e claim i s patentably d i s t i n c t over the r e f e e n c e s . A l l the o p e r pehding claims contain similar l i m i t a t i o n s . Therefore, Applicants request M a t a l l t h e

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Serial Number: 0832752.5 Art Unit: 1807

-5-

Claims 60-105 are allowable over the prior art of record-.The closest prior-art of record is Weiss and Stockham who teach equations and formulas for sharpening signal peaks derived from
electrophoretic,migration patterns of nucleic acid ladders. Weiss

.and Stockham do not teach or fairly suggest a method if inputting probe intensities to identify an unknown base where the probe intensities indicate the extent of hybridization of probes diffeging by a single base and the same nucleic acid as recited
$1)

che base claim, claim 6 0 .

No claims are allowed.

Papers related to this application may be submitted to Group
180O.by facsimile transmission via the P.T.O. Fax Center located in Crystal Mall 1 . The CM1 Fax Center number i s (703) 305-7401.

Please note chat the faxing of such papers must conform with the. notice to Comply published in the Official Gazette, 1 0 9 6 OG 30 (Nov 15, 1 9 8 9 ) An inquiry regarding this c o m m ~ c a t i o nshould be directed to examiner Dianne Rees, Ph.D., whose telephone number is (703) 308-6565. If'attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, W. Gary Jones, can be reached on (703) 308-1156. Calls of a general nature may be directed to the Group receptionist who may be reached at ( 7 0 3 ) 3081-0196.

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Dianne Rees July 8, 1996