`
`Serial No. 08/146,206
`PageS
`
`•
`
`Therefore, according to the teachings of Queen eta/., human framework region sequences
`
`needed to be tailored to each non-human antibody to be humanized. Furthermore, this
`
`reference taught that the heavy chain and light chain used for humanization should be derived
`
`from the same human antibody.
`
`Applicants submit that the invention recited in independent claims 1, 7, 15 and 22 herein differs
`from the teachings of each of the cited references in that it provides humanized antibodies
`
`wherein the heavy chain framework region of the humanized antibody is provided by a
`
`consensus human variable domain of a human heavy chain immunoglobulin subgroup, such as
`
`the VH subgroup Ill consensus human variable domain, e.g., of SEQ ID N0:4. The references
`cited by the Office fail to disclose or suggest the use of such a heavy chain consensus human
`
`variable domain.
`
`First, Applicants will comment on the statement by the Examiner that "there is no
`
`functional/structural distinction from what applicant has claimed and that taught by the
`
`combination of references." As noted above, independent claims 1, 7, 1.S and 22 herein recite a
`
`"consensus human variable domain of a human heavy chain immunoglobulin subgroup." As
`
`noted on page 1.S, lines 1.S-2.S of the application, consensus sequences (i.e., most commonly
`
`occurring residue or pair of residues) of human heavy chain immunoglobulin subgroups are
`
`compiled in Kabat eta/., Sequences of Proteins of Immunological Interest, Fourth Edition, U.S.
`Dept. of Health & Human Services, pubs., (1987). Kabat eta/. grouped various heavy and light
`chain variable domains according to their amino acid sequence identity to form several human
`
`immunoglobulin subgroups, i.e., human kappa light chains subgroups I to IV, human lambda
`light chains subgroups I to VI and human heavy chains subgroups I to Ill (see pages 41-76 and
`
`160-175 of Kabat eta/., copies attached}. The "occurrences of most common amino acid" (i.e.,
`
`"consensus human variable domain" of the instant claims) at each position of the variable
`
`domain are provided in the second to last column for each immunoglobulin subgroup in Kabat et
`
`a/. The cited references fail to disclose or suggest the use of a consensus human variable
`
`domain of a human heavy chain immunoglobulin subgroup having such an amino acid sequence
`
`in antibody humanization. Thus, Applicants submit that the heavy chain framework region of the
`
`claims herein, in fact, is structurally distinct from the framework regions of the cited references.
`
`PFIZER EX. 1502
`Page 2501
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`•
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`Serial No. 08/146,206
`Page9
`
`••
`
`Second, with respect to the Examiner's comment that a modification in the framework regions
`which affects the proximity or orientation of the VL-VH interface regions is the same as
`substituting that FR residue from the import regions that is involved in the effects set forth in
`
`paragraph (f) of claim 1, Applicants respectfully invite the Office to point out where exactly the
`
`references teach the invention set forth in part (f)(3) of claim 1.
`
`Finally, concerning the allegation that Riechmann et a/. teaches reduced immunogenicity
`
`associated with the humanized antibody, Applicants enclose a copy of Isaacs eta/. The Lancet
`
`340:748-752 (1992). Isaacs eta/. demonstrate that three out of four patients treated with
`
`Riechmann's humanized CAMPATH-1H antibody developed antiglobulins that were able to
`
`inhibit the binding of CAMPATH-1H to its antigen (see first paragraph of the discussion on page
`
`751 of this reference). On the contrary, repeated administration (i.e., loading dose and 10
`
`weekly doses) of the humanized anti-HER2 antibody (huMAb4D5-8) of Example 1 of the instant
`
`application has not lead to an immunogenic response in patients treated therewith (i.e. no
`
`antibodies against rhuMAb HER2 were detected in any patients). See abstract of Baselga eta/.,
`
`J. Clin. Oncol. 14(3):737-744 (1996), copy attached. Likewise, multidose administrations of an
`
`anti-lgE antibody humanized according to the teachings of the instant application and having a
`
`consensus human variable domain as claimed herein, did not induce a human antihuman
`
`antibody response in any of the patients treated therewith (see column 1, last paragraph on
`
`page 311 of Shields eta/., Int. Arch. Allergy lmmunol. 107:308-312 (1995), copy attached).
`
`These data point to the functional distinctness of the claimed consensus, human variable
`
`domain.
`
`In addition to the desirable lack of immunogenicity of the claimed humanized antibodies, as is
`
`apparent from the examples, the binding affinity of an antibody humanized using the claimed
`
`method is essentially retained and in some instances is improved in the humanized antibody
`
`compared to the non-human antibody from which it was derived. As shown, for example, in
`Table 3 of Example 1, anti-HER2 humanized variants huMAb4D5-6 and huMAb4D5-8 had
`
`binding affinities which were superior to the murine antibody from which they were derived. This
`
`could not have been predicted from the prior art, especially from Queen eta/., which advocated
`
`PFIZER EX. 1502
`Page 2502
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`•
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`Serial No. 08/146,206
`Page 10
`
`•
`
`the best-fit method (see above) and incorporated many (i.e., 15; see Figure 2) murine residues
`
`back into the humanized sequence to generate a "high affinity" humanized antibody. The above(cid:173)
`
`mentioned anti-HER2 variants, on the other hand, had only five FR substitutions and were not
`
`generated using the "best-fit" method said to be essential by Queen et a/.
`
`The instantly claimed invention has other novel and non-obvious features. For example, claim 2
`
`involves retaining the human residue, where the corresponding non-homologous import residue
`
`is exposed on the surface of the domain. The cited references fail to describe anywhere such a
`
`step. Claim 3 is independently patentable, as will be elaborated below. Claim 4 involves
`
`replacing consensus glycosylation sites which are not present in the import sequence with the
`
`corresponding import residue. The references are silent as to such a step. Similarly, the
`
`references fail to describe the additional step of claim 5 of the instant application. Also, the FR
`
`residues which can be substituted as now listed in claims 6, 7 and 1 0 are not disclosed in the
`
`cited references. Thus, Applicants submit that the invention recited in the claims of the instant
`
`application is clearly non obvious over the cited references.
`
`Accordingly, Applicants request that the above section 103 rejection be withdrawn.
`
`§103 -In re Durden
`Claims 1, 2, 4-12 and 15 and renumbered claims 19-22 and 24-25 stand rejected under 35 USC
`§103 as being unpatentable over the Winter patent application, Riechmann et al. and Queen et
`
`a/. in view of In re Durden 226 USPQ 359 (Fed. Cir. 1985).
`
`The Examiner states that the claimed methods for producing humanized antibodies and for
`
`humanization do not appear to differ from what was disclosed in the references. For the
`
`reasons given in the previous section, Applicants submit that the instantly claimed methods for
`
`humanization and the humanized antibodies are clearly different from what was disclosed in the
`
`cited references, especially with respect to the consensus human variable domain forming the
`
`FR of the humanized antibody.
`
`PFIZER EX. 1502
`Page 2503
`
`
`
`•
`
`Serial No. 08/146,206
`Page 11
`
`•
`
`Further, the Examiner is respectfully referred to the recent CAFC decisions of In re Brouwer, 37
`
`USPQ2d 1663 (Fed. Cir. 1996) and In re Ochiai, 37 USPQ2d 1127 (Fed. Cir. 1995). These
`
`cases stand for the proposition that a prima facie case of obviousness cannot be based on
`Durden, but rather needs to rest on particularized findings. It was held in Brouwer that there are
`
`no Durden obviousness rejections per se, only sec. 103 obviousness rejections. In the case of
`the instant claims, where the particular end product is unobvious, these. cases hold that the
`
`method of making them is also unobvious. In this regard, the Examiner is referred to the Official
`
`Gazette notice of 3/26/96, copy enclosed, which establishes guidelines for PTO personnel and
`
`the public on the proper consideration of method claims in light of these cases. In this Notice, it
`
`is stated that:
`
`[l]nterpreting a claimed invention as a whole requires consideration of all claim
`limitations. Thus, language in a process claim which recites making or using a
`nonobvious product must be treated as a material limitation, and a motivation to
`make or use the nonobvious product must be present in the prior art for a § 1 03
`rejection to be sustained.
`
`In light of Ochiai and Brouwer, Office personnel will consider all claim limitations
`when analyzing process claims which make or use nonobvious products under §
`103. Office personnel will focus on treating claims as a whole and follow the
`analysis set forth in Graham v. John Deere, 383 U.S. 1, 148 USPQ 459 (1966).
`(emphasis in original)
`
`Therefore, since there is no motivation in the cited art, as a whole, to make or use the
`
`nonobvious product, the claimed methods herein are non-obvious, and Applicants respectfully
`request that this rejection be reconsidered and withdrawn.
`
`§103- Claims 3 and 23
`
`Claim 3 and renumbered claim 23 stand rejected under 35 USC §103 as being unpatentable
`
`over the Winter patent application, Riechmann et a/. and Queen et a/. as applied to claims 1, 2,
`
`4-12, and 15 and further in view of Roitt et al., Immunology Gower Medical Publishing Ltd.,
`London, England, pg. 5.5 (1985) for the same reasons set forth in Paper #18.
`
`Applicants submit that claim 3 and FR substitution (c) of claim 23 clearly would not have been
`
`obvious in light of the cited references. The three primary references have been discussed
`
`PFIZER EX. 1502
`Page 2504
`
`
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`•
`
`Serial No. 08/146,206
`Page 12
`
`•
`
`above. Raitt et a/. merely shows that lgA 1 immunoglobulins may possibly have carbohydrate
`
`units in their variable domains. No such carbohydrate or oligosaccharide units are depicted in
`
`the diagrams of lgD and lgE variable domains in this reference. This reference is not concerned
`
`with antibody humanization, much less how to deal with glycosylation sites in humanization.
`
`In
`
`fact, the 4D5 antibody referred to in Example 1 is fairly unusual in that it has a glycosylation site
`
`in its variable region (i.e., residue number 65 of the light chain). As far as Applicants are aware,
`
`the instant application teaches, for the first time, how to deal with glycosylation sites in antibody
`
`humanization.
`
`Accordingly, Applicants submit that claim 3 and FR substitution (c) of claim 23 are clearly not
`
`obvious in light of the references cited and therefore respectfully request that the §103 rejection
`
`be withdrawn.
`
`Provisional double patenting rejection
`
`Claims 1-12, 15 and 19-25 are provisionally rejected under the judicially created doctrine of
`obviousness-type double patenting as being unpatentable over claims 1-12, 15 and 19 of
`
`copending application Serial No. 08/439,004. Given the provisional nature of this rejection,
`Applicants respectfully request that it be held in abeyance pending resolution as to allowable j X
`subject matter in this application or in the application on which this provisional rejection is based. j
`
`§102
`
`Claims 1-12, 15 and 19-25 are rejected under 35 USC §102(e) as being anticipated by US
`
`Patent 5,530,101 (the "101 patent"). With respect to claims 1-2 and 19-25, the Examiner is of
`
`the view that the 101 patent teaches methods for the production of humanized antibodies
`
`wherein the CDR amino acid sequences from the import/donor are exchanged for the
`
`human/acceptor CDR amino acid sequences, as well as the alignment of import and human
`
`framework regions and selection of substituted human framework antibody residues based on
`
`the following effects; the import framework residue noncovalently binds antigen directly, interacts
`with a CDR, or participates in the VL-VH interface. The Examiner asserts that the 101 patent
`
`teaches that, if a residue is exposed on the surface of the domain and does not have one of the
`
`effects of step (f) of claim 1, one should leave the human residue intact. The Examiner states
`
`PFIZER EX. 1502
`Page 2505
`
`
`
`•
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`Serial No. 08/146,206
`Page 13
`
`•
`
`that the term "consensus" has been interpreted to include the aligning of murine import
`
`framework residues to human acceptor framework residues, in addition to the aligning of all
`
`human framework residues and compiling a single "consensus" human framework. The
`
`Examiner comments separately on claims 3 and 4, 5, 6-8, 9, 10-12 and 15 and contends that
`
`these claims are also anticipated by the 1 01 patent.
`
`Applicants submit that the instantly claimed invention is not anticipated by the 101 patent for the
`
`reasons that follow.
`
`The 101 patent fails to teach the use, in antibody humanization, of a consensus human variable l
`
`domain, such as that of a human heavy chain immunoglobulin subgroup, as set forth in
`
`independent claims 1, 7, 15 and 22 herein. As to claim 1 (and FR substitution (d) of claim 23),
`the 1 01 patent further fails to teach the step of identifying and altering FR residues that
`
`participate in the interface between the light chain variable domain and the heavy chain variable
`domain of an antibody (i.e., the "VL-VH interface"). The Examiner takes the view that categories
`3, 4 and 5 in columns 14 and 15 of the 1 01 patent teach selection and substitution of such FR
`
`residues, but Applicants respectfully disagree. The FR residues to be identified in categories 3,
`
`4 and 5 of the 101 patent are those which "interact with amino acids in the CDR's", "interact
`
`directly with the antigen" or are "rare" for human sequences. There is no explicit teaching in the
`
`1
`\
`
`101 patent as to category (f)(3) of claim 1 or FR substitution (d) of claim 23 herein.
`
`)j.
`
`Hence, Applicants submit that independent claims 1, 7, 15 and 22 as well as FR substitution (d)
`
`of claim 23 are clearly novel over the 101 patent.
`
`As to the· other rejected claims, Applicants submit that they are further novel over the 101 patent
`
`for the reasons which follow.
`
`Claim 2 is concerned with determining whether non-homologous residues are exposed on the
`
`surface of the domain or buried within it. Where the non-homologous residue is exposed, the
`
`human residue is retained. Applicants submit that determining whether a residue is exposed on
`
`the surface of a domain or buried within it as recited in claim 2 is not the same as determining
`
`PFIZER EX. 1502
`Page 2506
`
`
`
`•
`
`Serial No. 08/146,206
`Page 14
`
`•
`
`whether a residue "interacts with a CDR". Applicants contend that the 101 patent in columns 13] ~
`
`14 does not teach the additional step of claim 2 of the instant application.
`
`With respect to claims 3 and 4 (as well as FR substitution (c) of claim 23}, Applicants submit
`
`that since the Examiner has failed to show where the 101 patent mentions glycosylation, let
`
`alone the invention recited in claims 3 and 4 and part (c) of claim 23, these claims must be novel
`
`over the 101 patent. If this rejection is to be maintained, Applicants request that the Examiner
`
`point out specifically where the 101 patent teaches the method steps of claims 3 and 4 and part
`
`(c) of claim 23 herein.
`
`As to claim 5, this refers to a step wherein non-homologous residues are identified and the
`
`human residue is used, where it represents a residue which is highly conserved across all
`
`species at that site. Category 2 in column 14 of the 101 patent refers, on the other hand, to
`using the "donor amino acid rather than the acceptor". Category 5 in the paragraph bridging
`
`columns 15-16 of the 101 patent suggests that neither the donor nor the, acceptor residue be
`
`used where the donor and acceptor residues are "rare". Clearly, the 101 patent fails to
`
`anticipate the method of claim 5 herein.
`
`Turning now to claims 6-8, the residues specifically mentioned as candidates for substitution in7 7)(
`column 15 of the 101 patent (to which the Examiner refers) have been removed from claim 6 j
`
`and claim 7 (on which claim 8 depends).
`
`.
`
`Concerning claim 9, Applicants submit that the 101 patent fails to enable the consensus human
`
`variable domain of this claim, but nevertheless the rejection is moot, due to the cancellation of
`
`claim9.
`
`With respect to claims 10-12, the residue positions mentioned in colum~ 15 of the 101 patent]
`have been removed from claim 10 (on which claims 11 and 12 depend).
`
`,f
`
`As to claims 19-21, Applicants submit that these claims are novel over the 101 patent, but they
`
`were canceled, and thus the §102 rejection is moot insofar as it applies to these claims.
`
`PFIZER EX. 1502
`Page 2507
`
`
`
`•
`•
`Finally, with respect to claims 24-25, Applicants submit that the Examples of the 101 patent J A.
`
`Serial No. 08/146,206
`Page 15
`
`require many more FR substitutions than "about 1 to about 5" as recited in these claims.
`
`Applicants submit that, for the reasons given above, claims 1-12, 15 and 19-25 are clearly novel
`over the 101 patent, and therefore respectfully request that this rejection be reconsidered and
`
`withdrawn.
`
`Applicants believe that the amendments and comments here put this case in condition for
`
`allowance. Nevertheless, should the Examiner have any further comments or questions, he is
`
`invited to call Wendy Lee at (415) 225-1994 concerning these.
`
`Respectfully submitted,
`GENENTECH, INC.
`
`By: ~2./~
`
`·
`
`Janet Hasak
`Reg. No. 28,616
`(for Wendy M. Lee
`Reg. No. 40,378}
`
`Date: June J ~ , 1997
`
`460 Pt. San Bruno Blvd.
`So. San Francisco, CA 94080-4990
`Phone: (415} 225-1994
`Fax: (415} 952-9881
`
`Enclosures:
`Isaacs et a/.
`Baselga et a/.
`Shields et a/.
`Kabat eta/.
`OG Notice of 3/26/96
`
`PFIZER EX. 1502
`Page 2508
`
`
`
`
`
`
`
`
`
`•
`
`•
`
`Leu Leu Ile Tyr Ser Ala Ser Phe Leu Glu Ser Gly Val Pro Ser
`50
`55
`60
`
`Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile
`65
`70
`75
`
`Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
`80
`85
`90
`
`His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
`95
`100
`105
`
`I1e Lys Arg Thr
`109
`
`(2) INFORMATION FOR SEQ ID N0:2:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 120 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:2:
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`Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
`1
`5
`10
`15
`
`Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys
`20
`25
`30
`
`Asp Thr Tyr I1e His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
`35
`40
`45
`
`Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr
`50
`55
`60
`
`Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser
`65
`70
`75
`
`Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
`80
`85
`90
`
`Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr
`95
`100
`105
`
`Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
`110
`115
`120
`
`(2) INFORMATION FOR SEQ ID N0:3:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 109 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:3:
`
`Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
`1
`5
`10
`15
`
`PFIZER EX. 1502
`Page 2512
`
`
`
`•
`
`•
`
`Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser
`20
`25
`30
`
`Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
`35
`40
`45
`
`Leu Leu Ile Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser
`50
`55
`60
`
`Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
`65
`70
`75
`
`Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
`80
`85
`90
`
`Tyr Asn Ser Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
`95
`100
`105
`
`Ile Lys Arg Thr
`109
`
`(2) INFORMATION FOR SEQ ID N0:4:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH:
`l20 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:4:
`
`Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
`1
`5
`10
`15
`
`Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
`20
`25
`30
`
`Asp Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
`35
`40
`45
`
`Glu Trp Val Ala Val Ile Ser Glu Asn Gly Gly Tyr Thr Arg Tyr
`I 50
`55
`60
`
`Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser
`. 65
`70
`75
`
`Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
`90
`80
`85
`
`Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr
`95
`100
`105
`
`Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
`110
`115
`120
`
`(2) INFORMATION FOR SEQ ID N0:5:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 109 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
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`PFIZER EX. 1502
`Page 2513
`
`
`
`•
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`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:5:
`
`•
`
`Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val
`1
`5
`10
`15
`
`Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn
`20
`25
`30
`
`Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly His Ser Pro Lys
`35
`40
`45
`
`Leu Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Thr Gly Val Pro Asp
`50
`55
`60
`
`Arg Phe Thr Gly Asn Arg Ser Gly Thr Asp Phe Thr Phe Thr Ile
`65
`70
`75
`
`Ser Ser Val Gln Ala G1u Asp Leu Ala Val Tyr Tyr Cys Gln Gln
`80
`85
`90
`
`His Tyr Thr Thr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu
`95
`100
`105
`
`Ile Lys Arg Ala
`109
`
`(2) INFORMATION FOR SEQ ID N0:6:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 120 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:6:
`
`Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly
`1
`5
`10
`15
`
`Ala Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys
`20
`25
`30
`
`Asp Thr Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu
`35
`40
`45
`
`Glu Trp Ile Gly Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr
`50
`55
`60
`
`Asp Pro Lys Phe Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser
`65
`70
`75
`
`Ser Asn Thr Ala Tyr Leu Gln Val Ser Arg Leu Thr Ser Glu Asp
`80
`85
`90
`
`Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr
`95
`100
`105
`
`Ala Met Asp Tyr Trp Gly Gln Gly Ala Ser Val Thr Val Ser Ser
`110
`115
`120
`
`PFIZER EX. 1502
`Page 2514
`
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`•
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`•
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`(2) INFORMATION FOR SEQ ID N0:7:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 27 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:7:
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`TCCGATATCC AGCTGACCCA GTCTCCA 27
`
`(2) INFORMATION FOR SEQ ID N0:8:
`
`(i) SEQUENCE CHARACTERISTICS:
`{A) LENGTH: 31 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
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`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:8:
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`GTTTGATCTC CAGCTTGGTA CCHSCDCCGA A 31
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`{2) INFORMATION FOR SEQ ID N0:9:
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`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 22 base pairs
`{B) TYPE: Nucleic Acid
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`(D) TOPOLOGY: Linear
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`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:9:
`
`f;
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`AGGTSMARCT GCAGSAGTCW GG 22
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`(2) INFORMATION FOR SEQ ID N0:10:
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`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 34 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
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`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:10:
`
`TGAGGAGACG GTGACCGTGG TCCCTTGGCC CCAG 34
`
`(2) INFORMATION FOR SEQ ID N0:11:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 36 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:11:
`
`PFIZER EX. 1502
`Page 2515
`
`
`
`•
`
`•
`
`GTAGATAAAT CCTCTAACAC AGCCTATCTG CAAATG 36
`
`(2) INFORMATION FOR SEQ ID NO:l2:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 36 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:12:
`
`GTAGATAAAT CCAAATCTAC AGCCTATCTG CAAATG 36
`
`(2) INFORMATION FOR SEQ ID N0:13:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 36 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l3:
`
`GTAGATAAAT CCTCTTCTAC AGCCTATCTG CAAATG 36
`
`(2) INFORMATION FOR SEQ ID NO:l4:
`
`fl
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 68 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l4:
`
`CTTATAAAGG TGTTTCCACC TATAACCAGA AATTCAAGGA TCGTTTCACG 50
`
`ATATCCGTAG ATAAATCC 68
`
`(2) INFORMATION FOR SEQ ID NO:l5:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 30 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l5:
`
`CTATACCTCC CGTCTGCATT CTGGAGTCCC 30
`
`(2) INFORMATION FOR SEQ ID NO:l6:
`
`PFIZER EX. 1502
`Page 2516
`
`
`
`•
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 107 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`•
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID
`
`N0:16:
`
`Asp Ile Gln Met Thr Gln Thr Thr Ser
`1
`5
`
`Ser Leu Ser Ala Ser Leu
`10
`15
`
`Gly Asp Arg Val Thr Ile Ser Cys Arg
`20
`
`Ala Ser Gln Asp Ile Arg
`25
`30
`
`Asn Tyr Leu Asn Trp Tyr Gln Gln Lys
`35
`
`Pro Asp Gly Thr Val Lys
`45
`40
`
`Leu Leu Ile Tyr Tyr Thr Ser Arg Leu
`50
`
`His Ser Gly Val Pro Ser
`55
`60
`
`Lys Phe Ser Gly Ser Gly Ser Gly Thr
`65
`
`Asp Tyr Ser Leu Thr Ile
`75
`70
`
`Ser Asn Leu Glu Gln Glu Asp Ile Ala
`80
`
`Thr Tyr Phe Cys Gln Gln
`85
`90
`
`Gly Asn Thr Leu Pro Trp Thr Phe Ala
`95
`
`Gly Gly Thr Lys Leu Glu
`100
`105
`
`Ile Lys
`107
`
`(2) INFORMATION FOR SEQ ID N0:17:
`
`(I
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 107 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Lin~ar
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:17:
`
`Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
`1
`5
`10
`15
`
`Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg
`20
`25
`30
`
`Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
`35
`40
`45
`
`Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser
`50
`55
`60
`
`Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
`65
`70
`75
`
`Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
`80
`85
`90
`
`Gly Asn Thr Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu
`95
`100
`105
`
`PFIZER EX. 1502
`Page 2517
`
`
`
`••
`
`Ile Lys
`107
`
`(2) INFORMATION FOR SEQ ID N0:18:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 107 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`•
`
`fl
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:18:
`
`Asp Ile Gln Met Thr Gln Ser Pro Ser
`1
`5
`
`Ser Leu Ser Ala Ser
`10
`
`Val
`15
`
`Gly Asp Arg Val Thr Ile Thr Cys Arg
`20
`
`Ala Ser Gln Ser Ile
`25
`
`Ser
`30
`
`Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
`35
`
`Pro Gly Lys Ala Pro
`40
`
`Lys
`45
`
`Leu Leu Ile Tyr Ala Ala Ser Ser Leu
`50
`
`Glu Ser Gly Val Pro
`55
`
`Ser
`60
`
`Arg Phe Ser Gly Ser Gly Ser Gly Thr
`65
`
`Asp Phe Thr Leu Thr
`70
`
`Ile
`75
`
`Ser Ser Leu Gln Pro Glu Asp Phe Ala
`80
`
`Thr Tyr Tyr Cys Gln
`85
`
`Gln
`90
`
`Tyr Asn Ser Leu Pro Trp Thr Phe Gly
`95
`
`Gln Gly Thr Lys Val
`100
`
`Glu
`105
`
`Ile Lys
`107
`
`(2) INFORMATION FOR SEQ ID N0:19:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 122 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:19:
`
`Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro
`5
`10
`1
`
`Gly
`15
`
`Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe
`20
`25
`
`Thr
`30
`
`Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn
`35
`40
`
`Leu
`45
`
`Glu Trp Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr
`50
`55
`
`Tyr
`60
`
`Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys
`65
`70
`
`Ser
`75
`
`PFIZER EX. 1502
`Page 2518
`
`
`
`•
`
`•
`
`Ser Ser Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp
`80
`85
`90
`
`Ser Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser
`95
`100
`105
`
`Asp Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val
`110
`115
`120
`
`Ser Ser
`122
`
`(2) INFORMATION FOR SEQ ID N0:20:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 122 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:20:
`
`Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
`1
`5
`10
`15
`
`Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr
`20
`25
`30
`
`Gly Tyr Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
`35
`40
`45
`
`Glu Trp Val Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr
`50
`55
`60
`
`Asn Gln Lys Phe Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser
`65
`70
`75
`
`Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
`80
`85
`90
`
`Thr Ala Val Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser
`95
`100
`105
`
`Asp Trp Tyr ~he Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val
`110
`115
`120
`
`Ser Ser
`122
`
`(2) INFORMATION FOR SEQ ID N0:21:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 122 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:21:
`
`Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
`15
`1
`5
`10
`
`PFIZER EX. 1502
`Page 2519
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`08/146,206
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`(e) [ ]
`
`•
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`•
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`Page2
`
`is filed after the mailing date of either a final rejection or a notice of allowance, whichever
`occurred first, and is accompanied by the fee ($130} setforth in 37 CFR §1.17{i)(1} and a
`certification as specified in 37 CFR §1.97(e}, as checked below. This document is to be
`considered as a petition requesting consideration of the information disclosure
`statement. The U.S. Patent and Trademark Office is hereby authorized to charge Deposit
`Account No. 07-0630 in the amount of $130.00 to cover the cost of this Information Disclosure
`Statement. Any deficiency or overpayment should be charged or credited to this deposit
`account. A duplicate of this sheet is enclosed.
`
`[If either of boxes (d) or (e) is checked above, the following "certification" under 37 CFR §1.97(e) may
`
`need to be completed.] The undersigned certifies that:
`
`[ ]
`
`[ ]
`
`Each item of information contained in the information disclosure statement was cited in a
`communication mailed from a foreign patent office in a counterpart foreign application not
`more than three months prior to the filing of this information disclosure statement.
`
`No item of information contained in this information disclosure statement was cited in a
`communication mailed from a foreign patent office in a counterpart foreign application or, to
`the knowledge of the undersigned after making reasonable inquiry, was known to any
`individual designated in 37 CFR §1.56(c) more than three months prior to the filing of this
`information disclosure statement.
`
`A list of the patent(s} or publication{s) is set forth on the attached Form PT0-1449 {Modified).
`
`A copy of the items on PT0-1449 is supplied herewith:
`[x] each [ 1 none [ ] only those listed below:
`
`Those patent{s) or publication(s) which are marked with an asterisk (*) in the attached PT0-1449 form are not
`
`supplied because they were previously cited by or submitted to the Office in a prior application Serial No. _
`
`_
`
`,filed
`
`and relied upon in this application for an earlier filing date under 35 USC §120.
`
`A concise explanation of relevance of the items listed on PT0-1449 is:
`
`[x]
`
`[ 1
`
`[ ]
`
`[ ]
`
`not given
`
`given for each listed item
`
`given for only non-English language listed item(s) [Required]
`
`in the form of an English language copy of a Search Report from a foreign patent office,
`issued in a counterpart application, which refers to the relevant portions of the references.
`
`The Examiner is reminded that a "concise explanation of the relevance" of the submitted prior art "may
`
`be nothing more than identification of the particular figure or paragraph of the patent or publication which has
`
`some relation to the claimed invention," MPEP §609.
`
`PFIZER EX. 1502
`Page 2521
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`f
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`..
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`'
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`08/146,206
`
`•
`
`•
`
`Page3
`
`While the information and references disclosed in this Information Disclosure Statement may be
`
`"material" pursuant to 37 CFR §1.56, it is not intended to constitute an admission that any patent, publication
`
`or other information referred to therein is "prior art" for this invention unless specifically designated as such.
`
`In accordance with 37 CFR §1.97(g), the filing of this Information Disclosure Statement shall not be
`
`construed to mean that a search has been made or that no other material information as defined in 37 CFR
`
`§1.56(a) exists. It is submitted that the Information Disclosure Statement is in compliance with 37 CFR §1.98
`
`and MPEP §609 and the Examiner is respectfully requested to consider the listed references.
`
`· Respectfully submitted,
`GE~~CH, INC.
`By: __ VJ_P_l~-"-'"""0""""-------
`
`WendyM. Lee
`Reg. No. 40,378
`
`Date: August aa_, 1997
`
`460 Pt. San Bruno Blvd.
`So. San Francisco, CA 94080-4990
`Phone: (415) 225-1994
`Fax: {415) 952-9881
`
`PFIZER EX. 1502
`Page 2522
`
`
`
`
`
`r
`
`FORM PT0-1449
`
`LIST OF DISCLOSURES CITED BY APPLICANT
`
`(Use several sheets if necessary)
`
`U.