DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s election without traverse of claims 75 and 80-86 (group III), drawn to a method of selecting a monoclonal antibody in the reply filed on 08/12/2025 is acknowledged.
3. Claims 1-63 and 65-71 are canceled.
Claims 64 and 72-86 are pending.
Claims 64, 72-74 and 76 to 79 are withdrawn from consideration under 37 CFR 1.142(b) as being drawn to nonelected invention and species.
Claims 75 and 80-86 are currently under examination.
4. Applicant' s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a divisional filing of US application 16/714,191 filed 12/13/2019, which is, in turn, a divisional filing of previous applications and ultimately claims priority benefit of U.S. provisional application 61/451,870 filed 03/11/2011. The elected invention appear to be supported throughout each of the parent applications; therefore, claims 75 and 80-86 have an effective filing date of 03/11/2011.
5. The information disclosure statements (IDSs) submitted on03/25/2025, 06/06/2024 and 08/12/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, these information disclosure statements are being considered by the examiner in their entireties.
Claim Rejections - 35 USC § 112
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.
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.
7. Claims 75 and 80-86 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.
Claim 75 recites the limitation "the 2C10 antibody" in line 3 of the claim. There is insufficient antecedent basis for this limitation in the claim. Claims 80-86 depend on claim 75 and are included in this rejection because these claims incorporate the indefiniteness of claim 75 by dependency.
Claims 75 and 80-86 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the CD40 epitope that is recognized by the antibodies. As recited, claim 75 only identifies the CD40 epitope as being recognized by “the 2C10 antibody” and omits the amino acid sequence and corresponding SEQ ID NO for the claimed epitope.
The preamble of claim 75 recites “A method of selecting a monoclonal antibody…” while parts (a) – (c) further limit this method by reciting steps including “recovering a pool of polyclonal antibodies”, “affinity purifying the pool of polyclonal antibodies”, and “resting the pool of polyclonal antibodies”. This does not appear to be a mistake in terminology or typographical error, because the claims are repeatedly drawn to a specific epitope recognized by a specific antibody clone; simultaneously, claims 83 and 84 further limit the “pool of polyclonal antibodies” as being recovered from a mammal, such as a mouse or rabbit. This claim is indefinite due to the combination of contradictory concepts and the examiner cannot understand what the applicant intends to claim. For instance, the well accepted method of generating a monoclonal antibody begins with inducing an immune reaction in a mammal (i.e., rabbit or mouse) by immunization with an antigen. Antibody producing B cells are then isolated from the mammal and fused to myeloma cells to create individual hybridoma cells, each capable of producing a unique antibody; these cells are isolated, expanded, assayed and selected for based on antibody production and antibody affinity characteristics. On the other hand, a pool of polyclonal antibodies will always be a mixture of antibodies produced by different B cells and are not understood to be a part of characterizing or selecting a monoclonal antibody. Therefore, claim 75 and 80-86 are indefinite because it is not clear what is being claimed.
8. 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.
9. Claims 75 and 80-86 are rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As claim 75 identifies the antibody epitope by the binding ability of the 2C10 antibody, it is apparent that said 2C10 antibody is required to practice the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the 2C10 antibody, or monoclonal hybridoma which produces this antibody, may satisfy first paragraph. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the 2C10 antibody has been deposited under the Budapest Treaty and that the 2C10 antibody will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806.
If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the 2C10 antibody described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
Further, amendment of the specification to disclose the date of deposit and the complete name and address of the depository (e.g. ATCC.10801 University Boulevard, Manassas, VA 20110-2209) is required as set forth in 37 C.F.R. 1.809(d).
10. Claims 75 and 80-86 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The scope of the claim
Base claim 75 recites “A method of selecting a monoclonal antibody comprising:
(a) recovering a pool of polyclonal antibodies that specifically bind a CD40 epitope recognized by the 2C10 antibody; (b) affinity purifying the pool of polyclonal antibodies with a polypeptide comprising the CD40 epitope; (c) testing the pool of polyclonal antibodies to determine a binding specificity by ELISA, western blot, or immunoprecipitation to identify a monoclonal antibody comprising a desired affinity for the CD40 epitope.”
Dependent claims 80-82 and 85-86 recite limitations drawn to the CD40 epitope, including limitations on the origin of the epitope (i.e., human), the length of the epitope, and specific amino acid sequences. Claims 83 and 84 recite limitations for the pool of polyclonal antibodies being recovered from a mammal and specifically a mouse or rabbit.
Therefore as recited, the claims are drawn to a method of selecting a monoclonal antibody (mAb) capable of binding to a singular and specific epitope sequence by purifying and assaying polyclonal antibodies. This method appears to encompass seemingly incompatible steps of divergent antibody technologies (i.e., polyclonal antibody VS mAb) and a skilled artisan would not know how to use this method with a reasonable expectation of success based on what is disclosed in the specification.
The amount of direction provided by the inventor and existence of working examples
The specification discloses a generalized approach of making mAbs by: 1) immunizing mice with a CD40 polypeptide fragment to generate an immune response; 2) isolating splenic cells; 3) forming a hybridoma by fusing isolated immune cells to myeloma cells; and 4) purifying the antibody produced by the hybridoma (e.g., pg. 4, last ¶ through pg. 5, first ¶). The specification also discloses approaches for identifying and selecting mAb secreting hybridomas based on antibody reactivity and binding affinity in vitro (see pg. 8, last ¶). The specification discloses a method cloning the variable regions of the mAb to recombinant constant chains (pg. 9) and methods for characterizing the mAbs by ELISA binding assay (pg. 10, ¶1). The specification further describes the effects of the mAbs on B cell activation (pg. 10-11), T cell-dependent antibody response (pg. 11-12) and in vivo efficacy of treating Rhesus macaques in allogenic islet transplantation model (12-13). Finally, the specification describes epitope mapping methods for determining binding site specific of the mAbs (pg. 14).
In addition to these approaches for generating and characterizing mAbs, the specification broadly describes several other approaches for making additional antibodies using fusion proteins comprising a CD40 antigen fragment (beginning pg. 14, last ¶). These methods include polyclonal antibody generation of rabbits (pg. 14, last ¶ through pg. 15, first ¶) and large scale polyclonal antibody generation in dairy cows or chickens (pg. 15, lines 26-31). The specification discloses that the antiserum obtained from these animals may be assessed for antibody specificity in vitro using similar methods that are used to determine mAb specificity, such as ELISA or western blotting (pg. 15, lines 9-12).
The specification fails to describe any methods for characterizing or selecting mAbs that involve polyclonal antibodies. The specification does not provide any guidance or rationale for combining these antibody technologies, especially in relying on antiserum antibodies that recognize a myriad of epitopes, and would not be able to provide any meaningful insight into the selection or characterization of mAbs.
The level of predictability in the art
Methods for generating mAbs date back nearly 50 years and are known in the art as a technological advancement and departure from polyclonal antibodies in several aspects. Liu, JK (Ann Med Surg (Lond). 2014 Sep 11;3(4):113-6. PMID: 25568796) teaches that mAbs are produced by a single B-lymphocyte and are monovalent, meaning they bind to the same epitope (pg. 114, section 2). A specific epitope of the desired antigen is used to immunize an animal to generate an immune response, then splenic B-lymphocytes obtained from the animal are fused to an immortal myeloma cell line; each individual clone can be separated by dilution into different culture wells with individual cells being screened for the desired antibody specificity (Liu, pg. 114, section 2). Over the years, a number of improvements to method of generating and selecting for monoclonal antibodies have been developed; for instant antigen-binding affinity can be improved by using phage display libraries to isolate antibodies with strong affinities for the antigen (Liu, pg. 114, section 5).
Recently, Alhazmi et al., (Pharmaceuticals (Basel). 2023 Feb 14;16(2):291. PMID: 37259434) reviewed analytical techniques for the characterization and quantification of mAbs, highlighting a litany of assays for identifying, characterizing and selecting desirable mAb clones by elucidating structural, physiochemical and immunological properties of individual mAbs (e.g., see table 1, beginning pg. 6).
While the clonal and biophysical diversity of polyclonal antibodies are particularly suited for many applications (Ascoli et al. Biotechniques. 2018 Sep;65(3):127-136. PMID: 30089399), multi-epitope binding and cross-reactivity is an inherent function of polyclonal antibodies (Ascoli, pg. 132, middle column). elucidating or identifying antibody epitope binding is not possible with polyclonal antibodies (Ascoli, pg. 134, middle column).
Regardless of the size or sequence of the antigen domain used for immunization, polyclonal antibodies have different structures, especially at the hypervariable regions (CDRs). One cannot predict the CDR structures of an antibody, or where epitope binding occurs. One cannot predict the epitope structure based on antibody structure either. In order to determine the structure of the generated antibodies they must be sequenced and the elucidation of epitope structures requires mutagenesis mapping, mass spectrometry, epitope binning experiments, or generation and evaluation of binding to epitope point mutants such as those as described by Alhazmi et al., Liu and many others. However, this would require method for single molecule sorting or a means for separating individual constituent antibodies from one another.
The quantity of experimentation needed to make or use the invention based on the disclosure
Based on the content of the disclosure in view of the divergent nature between polyclonal and monoclonal antibodies, a skilled artisan, through extensive trial-and-error experimentation, would have to generate entirely novel methods for isolating individual antibodies from one another before they would be useful in in the characterization and validation of a monoclonal antibody, as described by others. For all of these reasons, the specification does not enable one of ordinary skill in the art to make and/or use what is claimed and therefore claims 75 and 80-86 are rejected under 35 U.S.C. 112(a).
11. Claims 75 and 80-86 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claims contain 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(s), at the time the application was filed, had possession of the claimed invention.
This is a Written Description, New Matter rejection.
The method of selecting a monoclonal antibody comprising the steps (a) – (c), as recited in claim base claim 75 is not supported by the original disclosure or claim as filed.
Applicant’s amendment, filed 03/25/2022, directs to support for these claims to the specification as originally filed, and asserts that no new matter has been added.
However, the specification as filed does not provide sufficient written description of the above-mentioned method. The specification does not provide sufficient support for a method of selecting a monoclonal antibody comprising steps drawn to “recovering a pool of polyclonal antibodies” (claim 75a), or “purifying a pool of polyclonal antibodies” (claim 75b), or “testing the pool of polyclonal antibodies” (claim 75c).
The only methods of generating a monoclonal antibody that are disclosed in the present specification are those comprising the steps of administering a fragment of CD40 peptide to generate an immune response in a mammal, followed by isolating spleen cells from the mammal and forming a hybridoma to purify the antibody produced by said hybridoma (see specification pg. 4-5 and pg. 8-9; see also pg. 15 lines 13-19). None of these sections in the disclosure recite steps including the recovery, purification or analysis of pools of polyclonal antibodies. Rather, the instant specification only discloses methods of generating monoclonal antibodies and methods of generating additional antibodies (including polyclonal antibodies) as distinct, separate processes. For example, the only methods for generating polyclonal antibodies in the specification are disclosed in the section for “generation of additional antibodies” (beginning last ¶ of pg. 14). The specification explains that it is the immune sera that are subjected to assays for antibody titers and affinity purification (pg. 15, lines 1-12). Nowhere in the specification discloses a method of selecting a monoclonal anti-CD40 antibody by recovering a pool of polyclonal antibodies, affinity purifying the pool of polyclonal antibodies and identifying a monoclonal antibody from the pool of polyclonal antibodies.
Such limitations for the methods recited in the present claims, which did not appear in the specification, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C. 112.
Applicant is required to cancel the new matter in the response to this Office Action.
Alternatively, applicant is invited to provide sufficient written support for the “limitations” indicated above.
Conclusion
11. No claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES L MCLELLAN whose telephone number is (703)756-1906. The examiner can normally be reached Monday - Thursday 7:30 am - 5:30 pm. *Compressed day off on first Friday of each Bi-week.
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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.
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/JAMES LYLE MCLELLAN/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641