DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's election with traverse of the invention of Group II (claims 1-19, drawn to a fusion protein comprising an extracellular domain of CRIg or a fragment thereof; and a protein that specifically binds to VEGF, wherein the protein that specifically binds to VEGF comprises an extracellular domain of a VEGF receptor) in the reply filed on 02/17/2026 is acknowledged.
The traversal is on the grounds that the technical feature linking Groups I-III includes a fragment of CRIg extracellular domain which has “an activity equivalent to or similar to that of the extracellular domain of the CRIg,” as allegedly disclosed somewhere in the specification.
This is not found persuasive because, because Applicant’s argument is based on a limitation which is not claimed. The claims, as presently recited, place no structural or functional limitations on CRIg fragment. Therefore, the restriction requirement is still deemed proper.
The above notwithstanding, in the interest of compact prosecution the invention of Group I (claims 1-6 and 9-19, drawn to a fusion protein comprising an extracellular domain of CRIg or a fragment thereof; and a protein that specifically binds to VEGF, wherein the protein that specifically binds to VEGF comprises an anti-VEGF antibody) has been being fully examined for patentability under 37 CFR 1.104:
The restriction requirement between Groups I+II (claims 1-19) and Group III (claims 20 and 25) is made FINAL.
Applicant further elected, without traverse, the species of SEQ ID NO: 2. All species of the elected invention have been being fully examined for patentability under 37 CFR 1.104.
3. In view of the withdrawal of the restriction requirement as to the rejoined inventions, Applicant is advised that if claims directed to any of the rejoined inventions are presented in a continuation or divisional application, such claims may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
4. Claims 20 and 25 are withdrawn from further consideration by the Examiner under 37 C.F.R. § 1.142(b) as being drawn to nonelected inventions.
Claims 1-19 are presently under consideration.
5. In the event that claims 1-19 are deemed to be in condition for allowance, and applicant requests rejoinder of claims 20 and 25, applicant is invited to consider focusing the claims on treating specific eye diseases, such as AMD and/or CNV, to expedite prosecution. Upon cursory review, it appears that the specification does not provide a sufficient enabling description of a method of preventing eye diseases, or of a method of treating a generic eye disease.
6. 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.
7. Claims 4 and 13-15 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
(i) Claim 4 is indefinite in the recitation of “a DANG variation” and “an NG variation,” because the meaning of these terms is unknown. If they refer to amino acid substitutions, they are further indefinite because the identity of the “immunoglobulin fragment” is not defined.
(ii) Claim 13 is indefinite in the recitation of a fusion protein which “is” any one of the recited SEQ ID Numbers, because it is unknown whether the fusion protein consists of or comprises the recited sequences.
(iii) Claim 14 is indefinite, because the recitation of “the two fusion proteins” lacks proper antecedent basis in claim 1, which does not recite two fusion proteins.
(iv) Claim 15 is indefinite, because it encompasses the indefinite limitations of the claims on which it depends.
In view of the above, a person of ordinary skill in the art cannot unequivocally interpret the metes and bounds of the claims so as to understand how to avoid infringement. Applicant is reminded that any amendment must point to a basis in the specification so as not to add New Matter. See MPEP 714.02 and 2163.06.
8. The following is a quotation 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.
9. Claims 1-5, 9-12, 14-16 and 18-19 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contain(s) 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, at the time the application was filed, had possession of the claimed invention.
Specifically, the inventor or a joint inventor is not in possession of a generically recited “protein that specifically binds to vascular endothelial growth factor (VEGF)” (claim 1), or of a generically recited “antibody which specifically binds to VEGF” (claim 6).
The genera of VEGF-binding proteins and antibodies are defined solely by their function, without any limitations on the structure of the proteins of antibodies encompassed by the genera. While the specification exemplifies two classes of proteins within the scope of the genus, i.e. anti-VEGF antibodies and VEGF receptors, a skilled artisan would be aware that other types of VEGF-binding proteins may exist or may be artificially created.
It is well established in the art that the antigen-binding properties of antibodies are primarily, although not exclusively, determined by the amino acid sequences of their CDR regions, and that antibodies having a broad variety of CDR sequences can bind to the same epitope, compete with each other, and possess essentially the same antigen-binding and other functional properties See e.g. Khan et al. (2017), Konitzer et al. (2017), or Parola et al. (2018).
The written description requirement for a claimed genus may be satisfied either through sufficient description of a representative number of species, or by disclosure of relevant, identifying characteristics, i.e., structure or other properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics. MPEP 2163(II)(A)(3)(a)(ii).
A "representative number of species" means that the species which are adequately described are representative of the entire genus. For inventions in an unpredictable art, written description of a genus which embraces widely variant species must adequately reflect the structural diversity of the claimed genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP 2163(II)(A)(3)(a)(ii).
The specification discloses approximately 20 examples of monoclonal anti-VEGF antibodies ([0072] - [0092]).
As amply demonstrated by the references cited above, it is impossible for the skilled artisan to even estimate the size of the genus of possible CDR sequences of antibodies which can bind to the same epitope or compete for binding with the specified antibody, let alone visualize or recognize the identity of such sequences. As such, the outer boundary of the claimed genus is unknown, both in terms of size and structural diversity. Thus, neither applicant’s disclosure nor the knowledge in the art allows the skilled artisan to predict the undisclosed members of the genus. Accordingly, the disclosed antibodies are not representative of the structural diversity of the claimed genus.
Further, there is no “known or disclosed correlation” between the function of binding to a particular antigen, and the structural features which must be possessed by an antibody to accomplish this function. The specification does not disclose such correlation, and the teachings of the references cited above make it abundantly clear that at the present state of the art a skilled artisan cannot visualize or recognize the vast genus of possible CDR sequences which would endow an antibody with the recited properties. It is impossible for the skilled artisan to know in perfect detail the physiological and genetic backgrounds of all immune systems capable of producing antibodies, nor their prior immunological exposure. For example, Van Regenmortel (2018) highlights the difficulties inherent in immunological “inverse problems,” which start with the result (e.g. binding to an epitope) and then try to guess the multiple causes (i.e. structures) that could have produced it. According to Van Regenmortel, the extent of the immune system degeneracy, including the ability of numerous different antibodies and T cell receptors to bind to the same epitope, is still underappreciated.
To summarize, present specification does not describe a representative number of species or structural features common to the species encompassed by generic claims, nor is there a known or disclosed correlation between function and structure; therefore, the specification fails to satisfy the written description requirement of 35 U.S.C. 112(a).
10. 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.
11. Claims 1, 6, 16 and 18-19 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Graham et al. (US 20190343918; of record).
Claim interpretation: As pointed out in the previous office action, claim 1 recites a fusion protein comprising an extracellular domain of CRIg or a fragment thereof; and a protein that specifically binds to VEGF. Since the claim does not place any limitations on the nature or the size of the "fragment," any fragment, including fragments as short as one amino acid, is within the scope of the claim.
Response to applicant’s argument: Applicant argues that according to the specification, a fragment of CRIg extracellular domain has “an activity equivalent to or similar to that of the extracellular domain of the CRIg.” In response, it is improper to import claim limitations from the specification. See MPEP 2111.01(II).
Graham teaches VEGFR1 and VEGFR2 receptor fusion proteins (e.g. claims 1 and 4) which comprise at least one amino acid in addition to the VEGF receptor, thereby anticipating claims 1 and 6. Polynucleotides, vectors and transformed cells are inherent in the teachings of recombinant fusion proteins, therefore, claims 16, 18 and 19 are also anticipated.
12. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
13. Claims 1-3, 6-9, 12, 14-16 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Ashkenazi et al. (US 20070190054) and Her et al. (US 20180312819) (both cited on IDS).
Instant claims 1 and 9 are directed to a fusion protein comprising:
an extracellular domain of CRIg or a fragment thereof,
an immunoglobulin Fc domain, and
a protein that specifically binds to VEGF.
The claimed invention would have been obvious in view of Ashkenazi, who teaches combining complement-inhibiting CRIg-Fc fusion protein with a VEGF binding protein for treating AMD, and Her, who teaches fusion proteins comprising a complement inhibiting domain, an Fc domain and a VEGF binding domain for the same purpose.
Specifically, Ashkenazi teaches that CRIg-Fc fusion protein has complement-inhibiting activity (e.g. [0539]-[0541], [0562]), and is useful for treating age-related macular degeneration (AMD) (e.g. [0018], [0031]), where it can be combined with an anti-VEGF-A antibody, which is an angiogenesis inhibitor in showing promising results in clinical trials for AMD (e.g. [0209], [0355]). Ashkenazi claims the same in claims 22, 25, 26, 28, 42 and 43.
Ashkenazi further teaches that CRIg and Fc can be fused C-terminally or N-terminally (e.g. [0240]), may contain a linker between the CRIg and Fc (e.g. [0248]), and forms homodimers (e.g. [0245]). CRIg may also be fused to a complete antibody heavy chain, which may be fused to or associated with a light chain, thereby forming CRIg-antibody fusion (e.g. [0246]-[0247]). The Fc region may be a variant Fc region comprising amino acid substitutions (e.g. [0199]).
Her teaches bispecific fusion proteins that inhibit activation of complement pathway and VEGF pathway (e.g. the Abstract), comprising a complement inhibiting domain (CID), a VEGF inhibiting domain (VID), and a half-life prolonging domain (e.g. [0010]), wherein the VID comprises an extracellular domain of a human VEGF receptor and the half-life prolonging domain comprises an immunoglobulin Fc region (e.g. [0011]). The fusion proteins are particularly useful for treating AMD (e.g. [0156]).
Her further teaches that the VEGF receptor can be VEGFR-1 or VEGFR-2 (e.g. [0059]), a VID can also be an antibody that binds VEGF (e.g. [0060], [0061]), and the domains can be arranged from N-terminal to C-terminal as VID-Fc-CID or as CID-Fc-VID, connected by peptide linkers (e.g. [0011]).
To summarize, both Ashkenazi and Her teach a combination of a complement inhibitor-Fc fusion with a VEGF inhibitor for treating AMD, Ashkenazi exemplifying complement inhibitor as CRIg, and Her combining complement inhibitor-Fc and VEGF inhibitor into a single fusion protein. Based on this, a fusion protein combining CRIg, Fc and VEGF inhibitor would have been obvious to a person of skill in the art before the effective filing date of the claimed invention.
The expectation of success would have been provided by the routine nature of techniques used in constructing fusion proteins, and the motivation would have been provided by the teachings of both references regarding the desirability of inhibiting both complement and VEGF in treating AMD, and by the art-recognized need to improve AMD therapy.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
14. Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Ashkenazi et al. (US 20070190054) and Her et al. (US 20180312819), as applied to claims 1-3, and further in view of Lazar et al. (US 20180360981).
Claim 4 depends on claims 1-3, and specifies that the immunoglobulin fragment comprises “a DANG variation or an NG variation.” While the meaning of the “DANG” and “NG” abbreviations is unknown, as addressed in subsection 7(iv) above, it is provisionally assumed that NG variation may refer to an N-to-G amino acid substitution.
Claims 1-3 are obvious in view of Ashkenazi and Her, as addressed in section 13 above. While the cited references do not specifically exemplify N-to-G amino acid substitution in the immunoglobulin fragment of the fusion protein, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to introduce such substitution based on the knowledge in the art.
For example, Lazar teaches that reduced Fc effector function may be optimal for anti-VEGF antibodies (e.g. [0589], [0671]), and exemplifies N297G substitution as reducing Fc effector function. These teachings would have provided both the motivation and the expectation of success in introducing an “NG variation,” such as N297G substitution, into the anti-VEGF antibody portion of the claimed fusion protein.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
15. The following copending application shares a coinventor and/or an assignee with the present application, and discloses the subject matter of the present claims, but do not contain currently pending claims which would anticipate or make obvious the presently claimed invention:
USSN 18/726,333, published as US 20250074974, discloses a fusion protein of SEQ ID NO: 18, which is identical to SEQ ID NO: 2 (see SCORE) recited in instant claim 13.
16. The following prior art references, which contain teachings relevant to various aspects of the claimed invention, are cited of record but not presently relied upon:
US 20120107315 (cited on IDS)
US 20160326231 (cited on IDS)
US 20190071477 (cited on IDS)
US 20160271257
US 20220306736
US 20230348554
17. Claim 17 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all relevant limitations of the base claim and any intervening claims.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILIA I OUSPENSKI whose telephone number is (571)272-2920. The examiner can normally be reached 9 AM - 5:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ILIA I OUSPENSKI/ Primary Examiner, Art Unit 1644
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