DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
2. The information disclosure statements (IDS) submitted on 02/06/2023, 05/10/2023, 06/24/2024, and 06/24/2024 are acknowledged and the references cited therein have been considered.
Priority
3. The present application is a US Application, which claims the benefit of US Provisional Patent Application No. 63/284,991, filed 12/01/2021. Applicant' s claim for the benefit of prior-filed application is acknowledged.
Status of Claims
4. Applicant’s Response to Election/Restriction received 06/18/2026 is acknowledged.
5. Claims 1-4, 7-10, 13, 49, 51, and 53-64 are pending in the instant application.
6. Applicant’s election of Group I, claims 1-4, 7, and 13, (now claims 1-4, 7, 13, 51, and 56-60) with traverse, is acknowledged, which is directed to an antibody or antibody fragment, wherein the antibody or antibody fragment is an agonist of NRP1, and the species of SEQ ID NO: 205 as the VH and SEQ ID NO: 390 as the VL.
7. Applicant’s traversal is on the grounds that the Office has not shown that the burden imposed on the Office in examining Groups I to III and VII-IX together would be serious. This is not found persuasive because the specific Groups are comprised of polypeptide antibodies versus nucleic acids/vectors/host cell that are recognized divergent subject matter. In addition, the different inventions are distinct because their structures and functions are different and are therefore capable of separate manufacture, use and sale. By definition, an agonist in pharmacology is a chemical substance or drug that binds to a cell receptor and activates it to produce a biological response. In contrast, an antagonist in pharmacology is a drug or chemical that binds to a cell receptor without activating it, thereby blocking or reducing the biological response of an agonist. Thirdly, an allosteric modulator is a drug or substance that binds to a secondary (allosteric) site on a receptor to change its shape and alter its response to the primary agonist. Therefore, the Groups are distinct and independent, and searches of all Groups would place an undue burden upon the examiner due to the distinct and divergent subject matter of each Group. Further, a prior art search also requires a literature search. It is an undue burden for the examiner to search more than one invention.
The requirement is still deemed proper and is therefore made FINAL.
8. Claims 8-10, 49, 53-55, and 61-64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or species.
Claim Objections
9. Claims 2 and 57 are objected to for the phrase “a polyclonal antibody”, as it is not clear how a monoclonal antibody comprising a VH and VL could be polyclonal.
10. Claims 2 and 57 are objected to for the phrase “a camelized antibody”, as it is not clear how a monoclonal antibody comprising a VH and VL could be camelized and comprise only one VH (i.e., VHH).
11. The specification is objected to under 37 CFR 1.821(d) for failing to disclose SEQ ID NOs, for the amino/nucleic acid sequence disclosed in [00174], [00180].
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
12. Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 13 depends from claim 1 which recites the VH of the amino acid of SEQ ID NO:205, however, instant claim 13 fails to further limit instant claim 1 since it allows for up to 10% modification in the VH region of SEQ ID NO: 205 recited in the instant claim 1. Claim 13 broadens the limitation of claim 1. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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.
13. Claims 1-4, 7, 13, and 51 are 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 claims 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The scope of claim 1 encompasses a broad genus of NRP-1 binding antibodies, claiming a VH of SEQ ID NOs: 1-299 and a VL of SEQ ID NOs: 300-484.
Claims 2-4, 7, 13, and 51 are included because they depend from instant claim 1. Additionally, the scope of claim 13 encompasses a genus of antibodies that encompass up to 10% variant in the VH - including variations in the CDRs.
Neither the specification, nor the prior art provides any examples to support the premise of mixing and matching - VH/VL of different antibodies would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching a VH and a VL and result in functional anti-NRP-1 antibody. The specification fails to show that all VH and VL of antagonistic and agonistic anti-NRP-1 antibodies are equivalent. The specification fails to establish that by replacing at least one VH of one anti-NRP-1 antibody clone with another VH from a different anti-NRP-1 antibody clone, maintains NRP-1 binding. Mixing and matching different the VH/VL (comprising different CDRs) from different antagonistic and agonistic anti-NRP-1 antibodies has not been shown to lead to NRP-1 binding. Such teachings were not made part of the specification at the time the invention was made.
The instant application also encompasses (but does not exemplify) fragments and modification up to 10% (deletion/addition/substitution) to the claimed HCDRs of SEQ ID NOs: 1-299. There is no teaching identifying what amino acids can be varied within the VH-CDRs and/or VL-CDRs antibody regions and still retain antibody or fragments capable of binding space domain of NRP-1. Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. 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. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g. 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds the NRP-1 to satisfy the WD requirement for the claims.
With respect to the recitation of an antibody – up to 10% modification in the VH-CDRs of SEQ ID NO: 205 , the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provides the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Given the well-known high level of polymorphism of antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of antibodies encompassed in the claims at the time the instant application was filed.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
Allowable Subject Matter
14. Claims 56-60 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALAN ALFANO whose telephone number is (571)272-3092. The examiner can normally be reached M-F 8-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALAN ALFANO/Examiner, Art Unit 1641
/MAHER M HADDAD/Primary Examiner, Art Unit 1641
Prosecution Insights