•
`
`Serial No. 08/146,206
`Pages
`
`•
`
`Therefore, according to the teachings of Queen et al., 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, 1.5 and 22 herein recite a
`
`"consensus human variable domain of a human heavy chain immunoglobulin subgroup." As
`
`noted on page 15, lines 15-25 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 et al., Sequences of Proteins of Immunological Interest, Fourth Edition, U.S.
`
`Dept. of Health & Human Services, pubs., (1987). Kabat et al. 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 et al., 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.
`
`BIOEPIS EX. 1002
`Page 2501
`
`

`

`•
`
`Serial No. 08/146,206
`Page9
`
`e:
`
`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 al. teaches reduced immunogenicity
`
`associated with the humanized antibody, Applicants enclose a copy of Isaacs et al. The Lancet
`
`340:748-752 (1992). Isaacs et al. 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 (huMAb405-8) 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 et al.,
`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 et al., 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 huMAb405-6 and huMAb405-8 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 et al., which advocated
`
`BIOEPIS EX. 1002
`Page 2502
`
`

`

`•
`
`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 al.
`
`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 10 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
`
`al. 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.
`
`BIOEPIS EX. 1002
`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:
`
`[IJnterpreting 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 § 103
`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 al. and Queen et al. 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
`
`BIOEPIS EX. 1002
`Page 2504
`
`

`

`•
`
`Serial No. 08/146,206
`Page 12
`
`•
`
`above. Roitt et al. 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 405 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
`
`BIOEPIS EX. 1002
`Page 2505
`
`

`

`•
`
`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 101 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),
`
`\
`
`\
`
`)j.
`
`the 101 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 101 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
`
`101 patent as to category (f)(3) of claim 1 or FR substitution (d) of claim 23 herein.
`
`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
`
`BIOEPIS EX. 1002
`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] l
`
`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
`
`claim 9.
`
`,f
`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).
`
`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.
`
`BIOEPIS EX. 1002
`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 c2 ~ , 1997
`
`460 Pt. San Bruno Blvd.
`So. San Francisco, CA 94080-4990
`Phone: (415} 225-1994
`Fax: (415} 952-9881
`
`Enclosures:
`Isaacs et al.
`Baselga et al.
`Shields et al.
`Kabat et al.
`OG Notice of 3/26/96
`
`BIOEPIS EX. 1002
`Page 2508
`
`

`

`SERIAL NUMBER
`
`FILING DATE
`
`FIRST NAMED APPLICANT
`
`ATIORNEY DOCKETI NO.
`
`UNITED ST~~EPARTMENT OF COMMERCE
`Patent and Trademark Office
`Address: COMMISSIONER OF PATENTS AND TRADEMARKS
`Washington, D.C. 20231
`
`EXAMINER
`
`ART UNIT
`
`PAPER NUMBER
`
`DATE MAILED:
`EXAMINER INTERVIEW SUMMARY RECORD
`
`All participants (applicant, applicant's representative, PTO personnel):
`?JtFJ?~iCtc. Nt)LA/11
`c7s cAJ.JC!fe?uf:::.
`{!,Hlc/S
`(1 ) - - - - - -< - - - - - - - - - - - - - - - - - - - (3) ________________ ....._ ____ _
`
`{)J l;1J1) vf
`t.Zf;"
`(2 ) - - - - - - - - - - - - - , - - - - - - - - - - - - (4 ) - - - - - - - - - - - - - - - - - - - - -
`
`Date of Interview ---~-/_-z~,+.A_9_,_-_r_,__ _______ _
`
`Type: D Telephonic ~rsonai (copy is given to D applicant ~icant's representative).
`
`Exhibit shown or demonstration conducted: D Yes D No. If yes, brief des c r ip t ion : - - - - - - - - - - - - - - - - - - - - - - -
`
`Agreement o was reached with respect to some or all of the claims in question. ~ not reached.
`
`Claims d is cu ssed : - -~ / /_ / ;~ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`Identification of prior art d iscussed : - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`Description of the general nature of what was agreed to If an agreement was reached, or any other comments: _(17_.__ __ U)_tZ._~ __ ,a1'--_,t!i"""-~"-'-'------=--
`,t/p,~J ~ ,, Cbff~U,.a ti . ,
`/t<.4
`tpsrduu,.
`
`(A fuller de cription, if necessary, and a copy of the amendments, if available, which the examiner agreed would render the claims allowable must be
`attach
`Also, where no copy of the amendments which would render the claims allowable is available, a summary thereof must be attached.)
`
`. It is not necessary for applicant to provide a separate record of the substance of the interview.
`
`Unless the paragraph below has been checked to indicate to the contrary, A FORMAL WRITIEN RESPONSE TO THE LAST OFFICE ACTION IS NOT
`WAIVED AND MUST INCLUDE THE SUBSTANCE OF THE INTERVIEW (e.g., items 1-7 on the reverse side of this form). If a response to the last Office
`action has already been filed, then applicant is given one month from this interview date to provide a statement of the substance of the interview.
`
`D 2. Since the examiner's Interview summary above (including any attachments) reflects a complete response to each of the objections, rejections and
`requirements that may be present in the last Office action, and since the claims are now allowable, this completed form is considered to fulfill the
`response requirements of the last Office action. Applicant is not relieved from providing a separate record of the substance of the interview unless
`box1aboveisalsochecked.
`
`~ d~· ~
`
`PTOL-413 (REV. 2 -93)
`
`Examiner's Signature
`
`ORIGINAL FOR INSERTION IN RIGHT HAND FLAP OF FILE WRAPPER
`
`BIOEPIS EX. 1002
`Page 2509
`
`

`

`'•
`
`•
`
`Group Art Unit: 1816
`
`Patent Docket P0709P1
`·
`\
`IN Tt'~E UNITED STATES PATENT AND TRADEMARK OFFICE
`{
`
`----
`
`In re Application of
`
`Paul J. Carter et al.
`
`,\',
`
`Examiner: P. Nolan
`
`~ . -
`
`Serial No.: 08/146,206
`
`Filed: 17 November 1993
`
`n . .•••••n••••ngg,triiiJl+ti=st:Jiitt•.;HJMiv••••r• r>>-•······,-·,,,
`
`/u) 7/9 /
`
`For:
`
`METHOD FOR MAKING HUMANIZED
`ANTIBODIES
`
`1r11a11
`
`Assistant Commissioner of Patents
`Washington, D.C. 20231
`Sir:
`
`SUPPLEMENTAL AMENDMENT
`
`i\
`
`.. -~-·~--·
`___ .~_ .... --··
`•.. ..-. __ ~t:V
`~':-'C~~ _
`If ~'t;;.,,.
`_
`cl~ :a\ ·\ff 1•
`Please amend the application in the following respects:
`v S'~
`~
`IN THE SPECIFICATION:
`On page 9, line 1, please replace "muMAb4d5" with -muMAb4D5-. ~~~~
`On page 9, lines 206~ 3~se replace "huxCD3v9" with -huxCD3v1~.,- _:..--;--~:~-----·····
`On page 9, line 30, pleast((e'place·"20" with--26-.
`-~-
`/ __ ...... --
`
`On page 9, line 33, please ~e "(o)" with-(•)-.
`On page 84, line 29, please-rej)race "(Fig. 5)" with -(SEQ ID N0:20)-.
`On page 90, please substitute the "S~CE LISTING" with the enclosed paper copy of the
`
`"SEQUENCE LISTING".
`
`REMARKS
`
`This amendment is prepared for the purposes of introducing a substitute sequence listing into the
`
`application. Applicants have found that SEQ ID N0:20 from the previously submitted sequence listing
`
`corresponds to the heavy chain variable domain seqµence of huxCD3v9 (see page 84, line 29), whereas
`Figure 5 shows the sequence of huxCD3~1._J_he description of Figure 5 on page 9 has been corrected in
`
`this respect and the sequence of huxCD3v1 in Figure 5 is included in the substitute sequence listing as SEQ
`
`ID N0:26. Further typographical errors in lines 1 and 33 on page 9 are corrected herein. Furthermore,
`page 84, line 29 now refers to SEQ ID N0:20, the huxCD3v9 heavy chain variable domain sequence. In
`
`accordance with 37 C.F.R. §§1.821 (f) and (g), the undersigneq hereby states that the content of the paper
`I further state that this submission includes no
`and the computer readable sequence listings is the same.
`new matter.
`Respectfully submitted,
`
`Date:August ~q, 1997
`
`1 DNA Way_
`South San Francisco, CA 94080-4990
`Phone: (415) 225-1994
`
`GEN.~ECH, INC.
`
`By:_LtJ/U. ___ ~ - - - - - - - (cid:173)
`WendyM. Lee
`Reg. No. 40,378
`
`BIOEPIS EX. 1002
`Page 2510
`
`

`

`•
`
`/ I
`
`Antibodi;"
`
`I
`I
`
`/
`
`I
`I
`
`LISTING
`
`INFORMATION:
`
`(i) APPLICANT: Carter, Paul J.
`Presta, Leonard G.
`
`(ii) TITLE OF INVENTION: Method for Making Humanized
`
`(iii) NUMBER OF SEQUENCES: 26
`
`(iv) CORRESPONDENCE ADDRESS:
`(A) ADDRESSEE: Genentech, Inc.
`(B) STREET: 1 DNA Way
`(C) CITY: South San Francisco
`(D) STATE: California
`(E) COUNTRY: USA
`(F) ZIP: 94080
`
`(v) COMPUTER READABLE FORM:
`(A) MEDIUM TYPE: 3.5 inch, 1.44 Mb floppy disk
`(Bl COMPUTER:
`IBM PC compatible
`(C) OPERATING SYSTEM: PC-DOS/MS-DOS
`(D) SOFTWARE: WinPatin (Genentech)
`
`f'
`
`(vi) CURRENT APPLICATION DATA:
`(A) APPLICATION NUMBER: 08/146206
`(B) FILING DATE: 17-Nov-1993
`(C) CLASSIFICATION:
`
`(vii) PRIOR APPLICATION DATA:
`(A) APPLICATION NUMBER: 07/715272
`(B) FILING DATE: 14-JUN-1991_
`
`(viii) ATTORNEY/AGENT INFORMATION:
`(A) NAME: Lee, Wendy M.
`(B) REGISTRATION NUMBER: 40,378
`(C) REFERENCE/DOCKET NUMBER: P0709Pl
`
`(ix) TELECOMMUNICATION INFORMATION:
`(A) TELEPHONE: 650/225-1994
`(B) TELEFAX: 650/952-9881
`(2) INFORMATION FOR SEQ ID NO:l:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 109 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l:
`
`Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
`5
`10
`1
`
`Val
`15
`
`Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val
`20
`25
`
`Asn
`30
`
`la Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
`35
`40
`
`Lys
`45
`
`......
`
`1
`
`BIOEPIS EX. 1002
`Page 2511
`
`

`

`•
`
`•
`
`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
`
`Ile 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:
`
`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 Ile 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
`
`BIOEPIS EX. 1002
`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: 120 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
`
`BIOEPIS EX. 1002
`Page 2513
`
`

`

`•
`
`(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 Glu 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
`
`BIOEPIS EX. 1002
`Page 2514
`
`

`

`•
`
`•
`
`INFORMATION FOR SEQ ID N0:7:
`
`(21
`
`(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:
`
`TCCGATATCC AGCTGACCCA GTCTCCA 27
`
`(2) INFORMATION FOR SEQ ID N0:8:
`
`(i) SEQUENCE CHARACTERISTICS:
`{Al LENGTH: 31 base pairs
`(Bl TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:8:
`
`GTTTGATCTC CAGCTTGGTA CCHSCDCCGA A 31
`
`(2) INFORMATION FOR SEQ ID N0:9:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 22 base pairs
`(Bl TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:9:
`
`f;
`
`AGGTSMARCT GCAGSAGTCW GG 22
`
`(2) INFORMATION FOR SEQ ID N0:10:
`
`(i) SEQUENCE CHARACTERISTICS:
`(Al LENGTH: 34 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(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:
`
`BIOEPIS EX. 1002
`Page 2515
`
`

`

`•
`
`•
`
`GTAGATAAAT CCTCTAACAC AGCCTATCTG CAAATG 36
`
`(2) INFORMATION FOR SEQ ID N0:12:
`
`(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 N0:13:
`
`GTAGATAAAT CCTCTTCTAC AGCCTATCTG CAAATG 36
`
`(2) INFORMATION FOR SEQ ID N0:14:
`
`fl
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 68 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:14:
`
`CTTATAAAGG TGTTTCCACC TATAACCAGA AATTCAAGGA TCGTTTCACG 50
`
`ATATCCGTAG ATAAATCC 68
`
`(2) INFORMATION FOR SEQ ID N0:15:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 30 base pairs
`(B) TYPE: Nucleic Acid
`(C) STRANDEDNESS: Single
`(D) TOPOLOGY: Linear
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N0:15:
`
`CTATACCTCC CGTCTGCATT CTGGAGTCCC 30
`
`(2) INFORMATION FOR SEQ ID N0:16:
`
`BIOEPIS EX. 1002
`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 Ser Leu Ser Ala Ser Leu
`1
`5
`10
`15
`
`Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg
`20
`25
`30
`
`Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys
`35
`40
`45
`
`Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser
`50
`55
`60
`
`Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
`65
`70
`75
`
`Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln
`80
`85
`90
`
`Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly Thr Lys Leu Glu
`95
`100
`105
`
`Ile Lys
`107
`
`(2) INFORMATION FOR SEQ ID N0:17:
`
`fl
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH: 107 amino acids
`(B) TYPE: Amino Acid
`(D) TOPOLOGY: Linear
`'
`(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