Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s representative called to question why claims 80-86 were not addressed in the prior Office Action. The undersigned stated that these claims were not considered due to an error. Applicant’s representative asked that a new Non-Final rejection be issued addressing pending claims 67-86.
The prior Office Action mailed 6-1-26 is hereby REVOKED.
The instant communication should restart applicant’s time period for response based on the mailing date of the instant communication.
Applicant’s 4-21-26 election of the species of the species corresponding to subpart (ii) of claim 67, i.e., a light chain variable region wherein the amino acid in position corresponding to position F10 in SEQ ID NO: 10 is not F, and wherein one or more of the amino acid positions corresponding to the positions T41, K55, and L97 in SEQ ID NO: 10 are not T, K, and L is acknowledged.
Claims 67-86 are pending and under examination as they read on the species corresponding to subpart (ii) of claim 67, i.e., a light chain variable region wherein the amino acid in position corresponding to position F10 in SEQ ID NO: 10 is not F, and wherein one or more of the amino acid positions corresponding to the positions T41, K55, and L97 in SEQ ID NO: 10 are not T, K, and L.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 67-76, 78, 79 and 85 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The metes and bounds of claim 67 and dependent claims thereof would be unclear to the ordinarily skilled artisan because, on the one hand, the beginning of claim 67 (“A nucleic acid comprising a nucleotide sequence encoding (a) a heavy chain and/or (b) a light chain of a humanized or chimeric antibody which binds to human CD3…”) suggests that the claimed nucleic acid may comprise ONLY a heavy chain OR ONLY a light chain (and not necessarily both), and, on the other hand, the claim goes on to recite that the “…humanized or chimeric antibody which binds to human CD3…comprises VH CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and a VL region comprising the amino acid sequence of SEQ ID NO: 10, but wherein…,” which seems to suggest that the claimed nucleic acid must at least encode the VH CDR1, CDR2, and CDR3 domains of SEQ ID NOs: 1, 2, and 3, respectively, AND ALSO encode at least a VL region comprising the amino acid sequence of SEQ ID NO: 10 having one or more point mutations as recited in parts (i)-(vi) of claim 67.
Similar language is present claim 85. On the one hand, the beginning of claim 85 (“nucleic acid comprising a nucleotide sequence encoding (a) a heavy chain and/or (b) a light chain of a humanized or chimeric antibody which binds to human CD3…”) suggests that the claimed nucleic acid may comprise ONLY a heavy chain OR ONLY a light chain (and not necessarily both), and, on the other hand, the claim goes on to recite that the “…humanized or chimeric antibody which binds to human CD3…comprises VH CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and a VL region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 10, but wherein…,” which seems to suggest that the claimed nucleic acid must at least encode the VH CDR1, CDR2, and CDR3 domains of SEQ ID NOs: 1, 2, and 3, respectively, AND ALSO encode at least a VL region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 10, but wherein the VL also has one or more point mutations as recited in parts (i)-(v) of claim 85.
Given the lack of certainty as to the metes and bounds of claims 67 and 85, for the purposes of examination under other statutes such as 35 USC § 102(a)(1)/(a)(2) and obviousness-type double patenting, claim 85, and claim 67 and dependent claims thereof will be considered as they read on a nucleic acid comprising ONLY a nucleic acid encoding the heavy chain VH CDR1, CDR2, and CDR3 domains of SEQ ID NOs: 1, 2, and 3, respectively, or as they read on a nucleic acid comprising ONLY a nucleic acid encoding a light chain comprising an amino acid sequence of SEQ ID NO: 10 having one or more point mutations as recited in parts (i)-(vi) of claim 67 / ONLY a nucleic acid encoding a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 10 wherein the VL also has one or more point mutations as recited in parts (i)-(v) of claim 85.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 67-79 and 85 are rejected on the ground of nonstatutory double patenting as being unpatentable over certain claims of certain U.S. Patent Nos. set forth below in view of Neijssen et al (20140170149) and Feng et al. (mAbs 2:5, 466-477; September/October 2010)(all cited on a prior 892).
patent #
ref claims
ref clm embodiments
10465006 (cited on an IDS)
1-19
drawn to anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
10544220 (cited on an IDS)
1-20
drawn to anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
10590206 (cited on an IDS)
11
drawn to anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11485796 (cited on an IDS)
9
drawn to a method of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11008399 (cited on a prior 892)
12-20
drawn to anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11130819 (cited on a prior 892)
1-24
drawn to anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11970544 (cited on a prior 892)
13, 14, 17-21, 24-31
drawn to methods of making a bispecific antibody comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, and drawn to nucleic acids encoding anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3 and expression vectors and host cells thereof, and further drawn to which may include the epcoritmab antibody
11535679 (cited on a prior 892)
1-27
drawn to a method of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11548952 (cited on a prior 892)
1-27
drawn to a method of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11608383 (cited on a prior 892)
1-30
drawn to a method of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11814437 (cited on a prior 892)
1-13
drawn to nucleic acids encoding anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3 and expression vectors and host cells thereof; methods of making with said host cells., which may include the epcoritmab antibody
11845805 (cited on a prior 892)
1-33
drawn to a method of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
11858995 (cited on a prior 892)
1-28
drawn to a method of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
12435154 (cited on a prior 892)
1-29
drawn to a method of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody
As set forth in the table above, the various sets of reference claims are drawn to:
anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody;
methods of treatment comprising administering anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody;
methods of making a bispecific antibody comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3, which may include the epcoritmab antibody; and
nucleic acids encoding anti-CD3 antibodies comprising a Vh of any one of SEQ ID NOs: 6-9 or comprising VH CDRs of SEQ ID NOs: 1-3 and expression vectors and host cells thereof, which may include the epcoritmab antibody.
With respect to the reference claims drawn to anti-CD3 antibodies that meet the structural limitations of the instant claims / to the methods of treatment comprising administering anti-CD3 antibodies that meet the structural limitations of the instant claims, it would have been obvious to one of ordinary skill in the art to make nucleic acid sequences encoding said antibodies, expression vectors comprising said nucleic acid sequences, and host cells comprising said nucleic acid sequences given the teachings of Neijssen.
In particular, Neijssen teaches a bispecific antibody comprising Her2 and CD3 binding regions, and further teaches nucleic acid sequences encoding said antibodies, expression vectors comprising said nucleic acid sequences, and host cells comprising said nucleic acid sequences at paras 83, 624-632 and exemplifies such in working Example 1.
Given the reference claims and the teachings of Neijssen it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to make nucleic acid sequences encoding the antibodies of the reference patents, expression vectors comprising said nucleic acid sequences encoding the antibodies of the reference patents, and host cells comprising said nucleic acid sequences for the purpose of facilitate convenient, adequate production of said antibodies from a recombinant host cell modified with said nucleic acids / said expression vectors consistent with the well-known practice the antibody biopharmaceutical art as illustrated for example by Feng at pages 466-67.
Likewise, in practicing a method of making an antibody as recited in the reference claims,
one of ordinary skill in the art will be making use of the nucleic acids and host cell thereof of the instant claims.
Given the above, insofar as the reference claims set forth above fail to outright anticipate the claimed nucleic acid, expression vector and host cell comprising the claimed nucleic acid (which is true for some of the reference claims as set forth in the chart above), when the non-anticipatory reference claims are considered in the context of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 67-75, 77-79 and 85 are rejected under 35 U.S.C. 102(a)(1) / 102(a)(2) as being anticipated by Huang et al. (WO2012162067A2)(cited on an IDS).
Huang teaches nucleic acids encoding a CD3-binding antibody having the Vh CDRs recited in claim 67 and 85, see e.g., “h-mab2 VH-8”; SEQ ID NO: 50, which comprises the VH CDRs 1-3 of SEQ ID NOs: 1-3 of the instant claims as exemplified by the attached alignment of Huang SEQ ID NO: 50 (see Huang at paragraphs 240-241 and claim 1), as well as vectors comprising said nucleic acids and host cells comprising said vectors (see paragraphs at page 68-72).
Thus, the teachings of Huang anticipate the instant claims.
Note that claims 68-75 while specifying certain types of VL domains do not require that such a VL domain be present for a sequence to anticipate said claims, i.e., claims 68-75 still encompass in their breadth the embodiment which encompasses a “nucleic acid comprising a nucleotide sequence encoding (a) a heavy chain…of a humanized or chimeric antibody which binds to human CD3, wherein the antibody comprises VH CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2 and 3, respectively,…”
Claim(s) 67-75, 77-79 and 85 are rejected under 35 U.S.C. 102(a)(1) / 102(a)(2) as being anticipated by Kischel et al. (8236308) (cited on an IDS).
Kischel teaches nucleic acids encoding a CD3-binding antibody having the Vh CDRs recited in claim 67, see e.g., SEQ ID NO: 110, which comprises the VH CDRs 1-3 of SEQ ID NOs: 1-3 of the instant claims as exemplified by the attached alignment of Kischel SEQ ID NO: 110 (see Examples 18 and 19) with SEQ ID NO: 6 of the instant claims (see below):
PNG
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240
703
media_image1.png
Greyscale
as well as vectors comprising said nucleic acids and host cells comprising said vectors (see col. 24, 2nd and 3rd full paragraphs).
Thus, the teachings of Kischel anticipate the instant claims.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 85 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claim encompasses in its breadth “a nucleic acid comprising a nucleotide sequence encoding (a) a heavy chain and/or (b) a light chain of a humanized or chimeric antibody which binds to human CD3, wherein the antibody comprises VH CDR1, CDR2, and CDR3 domains comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and a VL region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 10…”
It appears that the only teaching of the specification directly relevant to the “at least 95% identical” language is at page 69, penultimate paragraph which suggests that the variants encompassed by “at least 95% identical” include “…deletions or insertions, preferably substitutions, such as conservative or non-conservative substitutions….”
Thus, claim 10 encompasses in its breadth variants having at least 95% identity to SEQ ID NO: 10, said variants having up to five deletions, insertions and/or conservative or non-conservative substitutions, wherein said nucleic acid encodes an antibody that binds to human CD3.
Note that five deletions, insertions and/or conservative or non-conservative substitutions are sufficient, for example, to completely change the majority of amino acid residues in the VL CDR1 or in the VL CDR3 domains of SEQ ID NO: 10 (see SEQ ID NOs: 4 and 5), or to change all of the amino acid residues in the CDR2 of SEQ ID NO: 10 (“GTN”).
Note further that according to the Gemini AI model:
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397
653
media_image2.png
Greyscale
Thus, claim 85 encompass in its breadth nucleic acids encoding CD3-binding antibodies having VL CDRs comprising appx. 1.5x107 – 3x108 variants, which is around the number of stars that have been visualized in our galaxy (see Robert Lea, “This is the largest and most detailed image of our Milky Way — with over 60 million stars and 50 exoplanet systems,” 6-24-26, obtained from space.com, pages 1-5, cited herewith).
The instant specification exemplifies a single VH CDR3 substitution (L97H of SEQ ID NO: 10) which does not appear to effect CD3 binding (see Table 3 at rows 2, 5 and 7; see also SEQ ID NOs: 5 and 60).
Such a disclosure is insufficient to represent the breadth of nucleic acids encoding heavy and variant light chains as claimed that bind to human CD3.
Disclosure of a single VH CDR3 substitution (L97H of SEQ ID NO: 10) is not representative of the breadth of molecules contained within the claimed genus because any number of VL CDR residues are expected, a priori, to contribute to antigen binding and yet the instant specification and the knowledge in the art do not establish which residues of the disclosed VL CDRs are structurally essential to antigen binding versus those that are tolerant to change, and to what degree, i.e., conservative or radical.
To illustrate this point, consider Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28, cited on an IDS) which teaches “[t]he specificity and affinity of an antibody for its cognate antigen is determined by the sequence and structure of the variable fragment (Fv): a heterodimer consisting of the N-terminal domains of the heavy and light chains. Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” (see, page 416, column bridging paragraph, emphasis added).
Vajdos goes on to teach that "[b]y analyzing panels of point mutants, a detailed map of the
binding energetics can be obtained, but the process can be very laborious because individual
mutant proteins must be made and analyzed separately. In particular, a comprehensive analysis
of an antigen binding site would ideally encompass all CDR residues, and this would require the
analysis of dozens or even hundreds of point mutants." (see page 416, right column, first
paragraph). Vajdos solution to this dilemma was to make use of a shotgun scanning mutagenesis
which "uses phage displayed libraries of protein mutants constructed using degenerate codons
with restricted diversity." While this method of making libraries of mutants representative of the
potential antigen binding CDR residues was an improvement over previous strategies as taught
by Vajdos, it nonetheless required extensive experimentation to comprehensively scan the
potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427,
Materials and Methods.)
Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR
residues from the particular anti-ErB2 antibody under study, Vajdos would still not have been
able to say which CDR residues were actually involved in antigen binding, and which were
involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the
heavy and light chains as a whole, without the structure of the unbound antigen-binding site of
the antibody to aid in their analysis (see, in particular, Discussion, pages 422-425).
Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all
CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to
antigen-binding to adequately predict which CDR residues can be changed, and to what extent,
or in what context of additional compensatory mutations in other regions of the antibody.
Moreover, given an amino acid substitution that ablated binding, without the crystal structure in
hand, still further experimentation would have been required to determine the flexibility in this
particular residue, i.e., it's general tolerance or intolerance to change.
As yet another example to illustrate the sensitivity of some antibodies to changes in their CDR residues, especially CDR3 consider the teachings of Bedouelle et al. (FEBS J. 2006 Jan;273(1):34-46, cited on an IDS). While Bedouelle did not comprehensively scan all the CDR residues of their antibody using a combination of alanine and homologous substitutions as shown in Vajdos, Bedouelle did examine the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a >100 fold drop in binding affinity (see Table 1). As described by Bedouelle, some of these loss of function mutations were hypothesized to have a direct effect on antigen binding while others were hypothesized to indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). Thus, the teachings of Bedouelle provide further illustration of the unpredictability of making mutations within the CDR region of an antibody.
Notably, while the teachings of Vajdos and Bedouelle demonstrate the unpredictable effects of even single amino acid changes on antibody – antigen binding, there is an additional level of unpredictability in the art associated with making multiple changes in any given CDR(s). In particular, even in those instances where one can show certain residues of a given CDR are generally tolerant of single amino acid changes, this does not necessarily mean a combination of single amino acid changes, even to the same residues shown to tolerate change when mutated in isolation, will be tolerated. As an example consider Brown et al. (J Immunol. 1996 May 1;156(9):3285-91, cited on an IDS) which describes how the Vh CDR2 in a particular antibody was generally tolerant of single amino acid changes; however, the antibody lost binding upon the introduction of pairs of single amino changes in the same region (see, in particular Tables I and II and column bridging paragraph on page 3290).
Additionally, as emphasized by the teachings of Colman (Research in Immunology, 145:33-36, 1994, cited on an IDS) the type of CDR amino acid substitution, i.e., conservative vs. non-conservative, is not necessarily a good predictor of antigen binding: "[t]he above examples paint a confusing picture of the specificity of antibody-antigen interaction. In one structural context, a very conservative substitution may abolish binding; in another, a nonconservative substitution may have very little effect on the binding affinity.” (see pg. 35, top of left column). Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79: 1979-1983, March 1982, cited on an IDS) provides another example of how even a conservative change to a single amino acid residue in a CDR region of an antibody can ablate antigen binding (see, for example, Abstract).
Given the above, the skilled artisan cannot predictably extrapolate from the disclosure of the instant specification to the breadth of bispecific antibodies encompassed by the instant claims.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of bispecific antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of nucleic acids comprising a VL region at least 95% identical to SEQ ID NO: 10 that encodes an antibody VL domain which, when paired with a VH domain comprising the CDR1, CDR2 and CDR3 domain of SEQ ID NOs: 1-3, respectively, will produce an antibody which binds to human CD3.
When the above is taken together it is evident that the teachings of the instant specification fail to provide sufficient direction or guidance to put the skilled artisan in possession of the claimed genus of nucleic acids comprising a VL region at least 95% identical to SEQ ID NO: 10 that encodes an antibody VL domain which, when paired with a VH domain comprising the CDR1, CDR2 and CDR3 domain of SEQ ID NOs: 1-3, respectively, will produce an antibody which binds to human CD3. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Applicant has not described the claimed invention sufficiently to show they had possession of the genus of nucleic acids encompassed by the claims.
Claims 80-84 and 86 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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