DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election without traverse of invention I in the reply filed on 12/12/2024 is acknowledged.
Claims 12 and 13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/12/24.
Claims 1, 2, 5-8, 11 and 14-20 are examined on the merits.
Response to Arguments
Applicant's arguments filed 9/3/26 have been fully considered but they are not persuasive. See response below.
Claim Rejections - 35 USC § 112
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.
(Prior Rejection Maintained and extended to additional limitations) Claims 1, 2, 5-8, 11 and 14-20 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 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 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 following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See BU Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire 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.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1, 2, 5-8, 11 and 14-20 are rejected for lacking adequate written support for a:
Claim 1: A composition comprising one or more pharmamers, each pharmamer comprising two or more immunologically active molecules attached to one or more multimerization domains, wherein the two or more immunologically active molecules comprise one or more mouse Fab fragments or full length IgG antibody molecules against human CD3 and/or one or more mouse Fab fragments or full length IgG antibody molecules against human CD28, and wherein the one or more multimerization domains comprise a dextran molecule; and
Claim 8: A pharmamer comprising (1) two or more immunologically active molecules, wherein the two or more immunologically active molecules comprise one or more mouse Fab fragments or full length IgG antibody molecules against human CD3 and one or more mouse Fab fragments or full length IgG antibody molecules against human CD28, and (ii) one or more multimerization domains comprising a dextran molecule, wherein the two or more immunologically active molecules are attached to the one or more multimerization domains.
Specifically, the antibodies for CD3 and/or CD28 lack adequate written support.
The dependent claims do not elaborate on the antibody molecules required by claims 1 and 8. More specifically, the dependent claims do not provide specific structural limitations for these antibodies.
In support of the claimed genus of an “two or more immunologically active molecules” and “mouse Fab fragments or full length IgG antibody molecules against human CD3 and/or … human CD28…”. The specification discloses 3 specific antibodies (OKT3, UCHT1 and 17A2) which bind CD3 and 3 specific antibodies (CD28.2, 9.3 and theralizumab) which bind CD28. No other examples of antibodies are disclosed, including mutants or variants thereof.
In addition, within the claimed limitation of immunologically active molecules and antibodies that function as such, the specification states: “In many applications, it will be advantageous that the pharmamer comprises one or more Immunologically active molecules. Immunologically active molecules are compounds that can modulate the immuno-activity of the pharmamer itself or the immune system as such, by affecting binding characteristics or effects of the pharmamer. A pharmamer can comprise several immunologically active molecules which can be the same or different. Immunologically active molecules are a subgroup of biologically active molecules for example proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, antibodies, MHC molecules, TCR’s and recombinant binding molecules to any of the foregoing, and combinations thereof.” [see page 33 of instant specification at lines 16-27] Of note, this identified section of the specification elaborates on the broad function of the claimed antibodies as they also function as immunologically active molecules, since such antibodies are able to “…modulate the immuno-activity of the pharmamer itself or the immune system as such, by affecting binding characteristics or effects of the pharmamer.” This would imply that the CD3 and CD28 antibodies are able to be immunologically active against the pharmamer, which comprises these antibodies and/or the immune system. As stated above, applicants have disclosed 3 specific antibodies (OKT3, UCHT1 and 17A2) which bind CD3 and 3 specific antibodies (CD28.2, 9.3 and theralizumab) which bind CD28, but these antibodies are not immunologically active against the pharmamer, rather, they bind to CD3 or CD28.
Thus, the application fails to provide a representative number of species of antibodies that can bind to CD3 or CD28 and/or also performing the functions of being immunologically active against the pharmamer.
Moreover, the decision arrived at in Amgen v. Sanofi, 598 US 594 (2023), supports expanded analysis of whether a claim drawn to an antibody being specific for an epitope, even a specific epitope, permits an applicant to pursue all possible antibodies that are capable of being produced against such an epitope. Presently, the claimed pharmamer possesses a mouse Fab or full length antibody molecule(s) against human CD3 and/or human CD28 is only defined by the ability to bind to these cellular proteins. In view of the fact patterns detailed in Amgen v. Sanofi, applicants are not in possession of a pharmamer with one or more mouse Fab fragments or full length IgG antibody molecules against human CD3 and one or more mouse Fab fragments or full length IgG antibody molecules against human CD28.
In view of this uncertainty and the lack of a representative number of examples of the claimed genus, the claims are rejected for lack of adequate written description support.
Response to arguments:
Applicant’s arguments have been fully considered, however, they are not persuasive.
In response, Applicant has amended claims 1 and 8 to state that the antibodies against CD3 and CD28 are mouse antibodies against human CD3 or CD28, and further that the antibodies are either Fab fragments or full-length IgG antibodies. Thus, the present claims specify certain structural features of the recited antibodies.
It would be inappropriate to require Applicant to specify the structures of even a representative number of species of the anti-CD3 and anti-CD28 antibodies at the level of amino acid sequences of their variable domains, because there are innumerable variants at that level of structure, every one of which still provides the feature that is an aspect of the presently claimed invention, namely binding to human CD3 or human CD28. Description of such a genus cannot be provided completely given the number of possible variants that would provide the required binding specificity. Description and claiming of only a portion of such a genus would be futile, because such claims could be easily designed around. Further, the sequence-level structure of the recited antibodies is not an inventive aspect of the present technology-it is merely a plug-and-play component. U.S. patent law has a longstanding tradition of making use of generic features in claims; however, a requirement that any use of a biomolecule requires complete description if its sequence totally destroys any possibility to claim a generic feature. In the present claims, the immunologically active molecules do have specified structure in that they are either mouse Fab fragments or full-length mouse IgG antibodies, and their structure is further specified, even if generically, by their binding specificity for either CD3 or CD28. The amount of specified structure is consistent with the recited function of the antibodies in the context of the claimed invention; greater specificity of structure cannot be provided without destroying the genus.
Further, the classes of antibodies recited in present claims 1 and 8 have been known and commercially available for many years. Indeed, the first monoclonal antibodies against both CD3 and CD28 were made using mouse hybridoma technology (consistent with the present claim limitation to mouse antibodies). FDA approved the use of a mouse antibody (OKT3) for use in humans to prevent organ transplant rejection in 1985. Similarly, mouse antibodies directed against CD28 (e.g., Clone 9.3 and Clone CD28.2 mouse antibodies) were produced in the 1980s and their use led to the discovery of the CD28 receptor as a co-stimulatory signal for T-cell activation. The history of mouse antibodies against CD3 and CD28 extends back at least 40 years, during which time they have become available as standard tools in immunology. As such, the further details of their structure are irrelevant for the present invention.
Therefore, this information does not aid in the explanation of what was known in the prior art and in applicant’s disclosure in order to overcome this rejection.
As stated in the previous Office action, while applicants have pointed to 3 specific antibodies (OKT3, UCHT1 and 17A2) which bind CD3 and 3 specific antibodies (CD28.2, 9.3 and theralizumab) which bind CD28, these species do not place applicants in possession of the genus of a composition comprising one or more mouse Fab fragments or full length IgG antibody molecules against human CD3 and one or more mouse Fab fragments or full length IgG antibody molecules against human CD28. Since the claimed mouse Fab fragments or full length IgG antibody molecules is against human CD3 or human CD28, this amendment to claims 1 and 8 still only describes what the antibody can bind without providing a structure of the antibody. Furthermore, the population of a mouse IgG antibodies is broad based on gene rearrangement within B-cells in vivo.
Collins et al. (Pharmacology and Therapeutics, 2003-see attached PTO-892 form) provides a summary of the gene rearrangement process for antibodies/immunoglobulins (see Figure 2 and section 2.1.2) that results in a diverse antibody population. Therefore, the amendments to the claims while limiting the antibody molecules to mouse IgG, this population of antibodies is broad and the claims do not provide specific structure (amino acid sequences) of an antibody molecule within the scope of the claims. Identifying the antibody molecule as mouse Fab fragments or full length IgG antibody molecules contrary to applicant’s statement that “Since any antibodies having such binding affinity are within the scope of claim 1, their specific structure is not relevant to the invention, and are not part of the invention.”, the claimed invention requires an antibody against CD3 or CD28, and therefore, are interpreted to be part of the invention. If applicants are suggesting that an antibody against CD3 or CD28 isn’t part of the invention, then it would appear that the claimed invention is only drawn to a composition comprising dextran.
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.
(Prior Rejections Maintained) Claims 1, 2, 5-8, 11 and 14-20 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
Claims 1 and 8 recite the limitation "…one or more mouse Fab fragments or full length IgG antibody molecules against human CD3 and one or more mouse Fab fragments or full length IgG antibody molecules against human CD28…”.
This limitation is unclear because “antibody” is defined as: “As used herein, the term "antibody" means an isolated or recombinant binding agent that comprises the necessary variable region sequences to specifically bind an antigenic epitope. Therefore, an antibody is any form of antibody or fragment thereof that exhibits the desired biological activity, e.g., binding the specific target antigen.” [see page 3, lines 21-25 of specification] Therefore, the word “antibody” includes monoclonal (mAb) and polyclonal antibodies (pAb) or fragments thereof. Therefore, the claim encompasses polyclonal antibodies with the six CDRs. However, polyclonal antibodies have many and different antibody species. The CDRs or variable regions could be found on one molecule in the pAb or two. The claim can be clarified by the following claim amendments: adding “monoclonal” to the limitation.
Appropriate correction is required. See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
Claims 2, 5-7, 11 and 14-20 are also rejected because they depend from claim 1 or 8, but do not remedy this deficiency.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
Applicant’s amendments do not clarify the claims since the recitation of "…one or more mouse Fab fragments or full length IgG antibody molecules against human CD3 and one or more mouse Fab fragments or full length antibody molecules against human CD28…” includes an indefinite grouping of antibodies, (monoclonal or polyclonal or fragments thereof)”. It is suggested that applicants amend the claims to recite, "…one or more mouse Fab fragments or full length IgG monoclonal antibody molecule against human CD3 and one or more mouse Fab fragments or full length IgG monoclonal antibody molecule against human CD28…”
Claims 1 and 8 recite: “wherein one or more multimerization domains comprise a dextran molecule”, however, it is unclear if the dextran molecule is the only molecule providing the one or more multimerization domains since the claim recites “comprise a dextran molecule”. Page 7, at lines 29-35 also state that such domains include polymers, proteins, micelles, cells, beads, etc.
Claims 2, 5-7, 11 and 14-20 are also rejected because they depend from claim 1 or 8, but do not remedy this deficiency.
*Applicant’s have not presented arguments against this rejection.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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