Detailed Action
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 election without traverse of Group I, claims 1-14, in the reply filed on 02/14/2025 is re-acknowledged.
Claims 15-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/14/2025.
Claims 1-20 are pending.
Claims 1 and 7-8 are amended.
Claims 1-14 are under examination on the merits.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/20/2026 has been entered.
Priority
This application’s claim of priority to U.S. Patent Application with the serial number 15/568,487, which was filed 10/23/20 17, which is a 371 Application of PCT/US2016/029244, which was filed 4/25/2016, and which claims priority to our U.S. Provisional Application Serial Number 62/178956, filed April 23, 2015, and U.S. Provisional Application Serial Number 62/159 145, filed May 8, 2015, is acknowledged.
Information Disclosure Statement
The IDS submission filed on 02/20/2026 has been considered by the Examiner in so far as the portion of the reference which was translated into the English language.
Maintained-Claim Interpretation
The newly added limitation of claim 1, “…wherein the synthetic antibody has a scaffold portion and a CDR graft portion…,”is being interpreted to reflect that the antibody is chimeric or humanized absent a clear, closed, and preclusive definition.
The specification only mentions a “high-diversity library” twice, providing the open definition that, “…a high-diversity library may be a phage display library having a diversity of at least 109 diverse members, or at least 1010 diverse members, or even higher, typically based on M13 phages and display via pIII, pVIII, pVI, or pIX, or based on T7 phages and the gene 10 capsid protein…,” (see for example, page 16 of the specification; see additionally page 5 of Applicant’s 02/20/2026 remarks).
Withdrawn Rejections
The rejections of claims 1-14 under 35 USC 112(b) are withdrawn as addressed by the corrective claim amendments dated 02/20/2026.
Claim Rejections - 35 USC § 112
Matintained-35 USC § 112(a)
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.
Claims 1-14 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 purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Even though Applicant has disclosed a vast number of cancer neoepitopes (see for example, instant SEQ ID NOs: 1 -1,408,729; see further for example, paragraph 0051 of the instant specification), Applicant fails to disclose a single antibody species within the claimed genus of antibodies binding a cancer neoepitope, the specification does not provide adequate written description for the entire claimed genus of species of antibodies, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences encompassed by the genus would function as claimed to bind the cancer neoepitopes. The amendments to the claim adding that the synthetic antibody has a CDR graft portion selected from an antibody of a high-diversity library, does not supply the written description required by the statue through indication of a structure/function correlation or a representative number of species. No conserved structure is indicated as required for the products, as claimed. Therefore, in view of this disclosure, Applicant is claiming a broad genus of molecules without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of antibodies (CDRs) binding any of the cancer neoepitopes, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences encompassed by the genus would function as claimed.
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 Eli 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. Applicant has not disclosed any CDR species for consideration. Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of no species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody the ability to function as claimed, because the instant specification does not provide structural antibody features that correlate with a functional ability to function in the claimed product(s).
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind a neoepitope as claimed. Rabia, et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example, increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind a neoepitope, as claimed. Thus, the claims need to specify the exact CDR1-6 sequence combination(s) of the claimed antibody.
Absent a description of the at least minimal structural features correlating with a functional ability to bind neoepitope(s) which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed antibodies may be combined such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of heavy and light chain CDR amino acid sequences it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require an antibody capable of binding to a cancer neoepitope. The specification does not describe which amino/nucleic acid residues of the administered antibody are responsible for the binding function claimed. Rather, the specification implicitly states that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. The specification fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant agents and fails to disclose which regions of the agents are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function to bind neoepitope as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some neoepitopes and then with a suggestion to raise a synthetic antibody against said neoepitope(s) that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular (neo)epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also 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.”
Therefore, the synthetic antibodies which bind cancer neoepitopes, as claimed, are only disclosed by function (binding), without a representative number of species or disclosure of sufficient unifying, conserved structure enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed to bind neoepitope. Therefore, the claims 1-14 are deemed to fail to meet the written description requirement, as presently drafted.
New-35 USC § 112(a)
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.
Claims 1-14 are further 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.
Note that the recitations of the standard for written description, boilerplate regarding Applicant’s burden to meet the written description requirement, and art cited in the maintained rejections for lack of written description under 35 USC §112(a) are incorporated herein.
Claim 1 recites that the antibody is bound to a synthetic immobilized peptide that has a sequence of a patient- and cancer- specific neoepitope. Claims 2-14 incorporate this limitation without further description or narrowing.
Claim 8-10 recite the broad genus of a therapeutic agent that is an affinity agent. This term is only mentioned 3 times in the disclosure with no examples and no definition of the term.
Where the therapeutic agent is coupled to an antibody binding a cancer neoepitope, the therapeutic agent is logically interpreted to be therapeutic for cancer. However, the genus of therapeutic affinity agents is reasonably interpreted as broad enough to encompass antibodies, aptamers, proteins, etc., particularly where no particular affinity is required (such as a target or even affinity of the agent for target). As this term is only mentioned 3 times in the specification, there is no disclosure of a representative number of species or descriptive disclosure of a structure correlated with the claimed therapeutic function.
See the maintained rejections under 35 USC §112(a) above for a discussion of why antibodies represent an unpredictable and evolving art such that the artisan could not reasonably, readily envisage the members/species of the genus having the claimed function(s) required.
As a further illustrative example, the Examiner will provide analysis for the subgenus of protein affinity agents which is simultaneously illustrative of the state of the art regarding the synthetic peptides to which the antibody is bound in claim 1.
Regarding the state of the art, Listov et al (Opportunities and challenges in design and optimization of protein function. Nat Rev Mol Cell Biol 25, 639–653 (2024)) teach that the primary amino acid sequence determines downstream structure (protein folding), which then determines function (presenting both the inverse folding problem and the inverse function problem (see for example Figure 1 and its caption; see also Mishra et al (Inaccurate secondary structure predictions often indicate protein fold switching. Protein Sci. 2019 Aug;28(8):1487-1493. doi: 10.1002/pro.3664. Epub 2019 Jun 17)). Expanding on these problems in proteomics, Reardon (Nature 635, 246-248 (2024)) explains that the goal of designing a protein with known and predictable function, binding partners, size, location, and other traits is, for the moment, a dream. Reardon teaches that further challenges in protein design include predicting how a protein, even if it binds to target, will function upon said binding. Reardon teaches that the primary structure (amino acid sequence) of a protein is critical to function, noting that even proteins of similar shape do not execute the same functions, while those with different shapes may carry out the same tasks. Reardon goes on to teach that it is not always apparent which parts of the primary sequence are important; a seemingly useless amino-acid chain on the side of an enzyme, for instance, might affect how tightly a protein can bind to other molecules or its ability to flip between conformational states. Moreover, Reardon explains that when researchers attempt to solve the structure of a protein experimentally, they often end up seeing only the most stable conformation, which is not necessarily the form the protein takes when it is active (see for example, pages, 246-247 of Reardon).
Therefore, the synthetic peptide of claim 1 (incorporated by claims 2-14) is inadequately described. Additionally, the therapeutic agent of claims 8-10 is inadequately described (where claims 1-7 are included in the rejections as being broader in scope and failing to narrow or describe the therapeutic agent).
New-Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-3 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wistar (US20100203109A1; as cited on the 03/13/2025 IDS) in view of Hacohen et al (Getting personal with neoantigen-based therapeutic cancer vaccines. Cancer Immunol Res. 2013 Jul;1(1):11-5. doi: 10.1158/2326-6066.CIR-13-0022. Epub 2013 Apr 7) and Huang et al (Antimicrob Agents Chemother. 2012 Sep;56(9):4569-82. doi: 10.1128/AAC.00567-12. Epub 2012 Jun 4).
Regarding claim 1, Wistar teaches antibodies (which may be therapeutic or diagnostic) (reading on a composition comprising antibodies as no other limitation is recited in the claims) which bind a cancer-specific neoepitope (BRAFV600E mutant peptides held to read upon the limitation of a cancer neoepitope, which is cancer-specific (tied to melanoma and not tied to any other diseases) absent a closed definition to further clarify or preclude this interpretation and given its consistency with the instant disclosure (see for example, paragraphs 0026 and 0029 of the instant specification)) where the antibody may be humanized or chimeric (see for example, the abstract, paragraphs 0090-0094 and 0120 of Wistar).
Wistar further teaches the process of using BRAF peptides, such as the mutated BRAF 29-mer having the V600E mutation (neoepitopes), for use in screening antibodies from libraries of antibodies to isolate antibodies that bind the neoepitope(s) (see for example, paragraphs 0004-0006, 0091-0092, and 0124-0125). Wistar further teaches that conventional drug screening techniques may be employed using the peptides described herein. As one example, a method for identifying compounds which specifically bind to a peptide include the steps of contacting a selected peptide with a test compound to permit binding of the test compound to the peptide; and determining the amount of test compound, if any, which is bound to the peptide. Such a method may involve the incubation of the test compound and the peptide immobilized on a solid support (see for example, paragraph 0126).
Wistar does not clearly teach that the neoepitope is personalized to the patient (but, in the absence of a closed/alternate/preclusive definition, the terms ‘patient-specific’ and ‘cancer -specific’ are being interpreted using their broadest reasonable interpretation: that the neoepitope is exhibited in the patient/patient’s cancer so as to be patient-specific and exhibited in the patient’s cancer/associated with a known cancer so as to be cancer specific) or HLA-matched.
However, Hacohen et al teach rapid DNA/RNA sequencing of tumor and normal tissue with further filtering for patient-specific (personalized), cancer-specific (tumor-specific) neoepitopes (mutated peptides) which are HLA-matched (identified on the basis of predictive HLA-binding algorithms) (see for example, the abstract, figure 1, and the caption of figure 1).
Wistar and Hacohen et al do not teach that the CDRs are selected from a high-diversity library.
However, Huang et al teach that phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens. The size and quality of libraries are crucial for the success of phage display. Currently, methods for the production of peptide libraries can lead to library sizes from 109 to 1011, with the average library generally containing 107 members. Optimized and novel strategies to generate large antibody libraries have been carried out, increasing the diversity to 1012, noting that M13 phage library display technology is well-known in the art (see for example, pages 4569-4751). Huang et al teach that advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens (see for example, page 4569 at the abstract and pages 4571-4573).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, and Huang et al. The artisan would have been motivated to make and use the invention as claimed because Wistar teaches means for raising synthetic, therapeutic antibodies against a cancer-specific neoepitope (see for example, the abstract, paragraphs 0090-0094 and 0120 of Wistar), using a library and screening such that the neoepitope is immobilized on a solid support. Where Wistar teaches the use of humanized antibodies, the artisan would have found it obvious to take CDRs from the screened library and graft them into a human antibody framework (a scaffold as is consistent with page 17 of the instant specification). Upon further screening to confirm continued specificity, the synthetic antibody having grafted CDRs from the high-diversity library of Wistar as modified by Huang et al in a human scaffold would have been bound to the neoepitope of Wistar as modified by Hacohen et al, said neoepitope being immobilized on a solid support (prior to isolation of the neoepitope-binding antibody). Using the process of Wistar for antibody generation, the artisan would have understood the desirability of selecting a neoepitope that is that is personalized (patient-specific), cancer-specific, and HLA-matched through the means taught by Hacohen et al (see for example, the abstract, figure 1, and the caption of figure 1). Hacohen et al further teach that despite years of preclinical efforts and hundreds of clinical studies, therapeutic cancer vaccines have been elusive, but with advances in genome sequencing, it is now possible to identify a new class of tumor-specific antigens derived from mutated proteins that are present only in the tumor which should provide highly specific targets for antitumor immunity (see for example, the abstract of Hacohen et al). The artisan would have further found it obvious, to modify the library used in Wistar to be a high-diversity library in order to enable for better generation and screening of antibodies as taught by Huang et al (noting that even the average phage library generated by traditional means comprises 107 members while many technologies yield library sizes from 109 or more, with larger sized being desirable, noting that optimized techniques yield libraries with 1012 members). Where the library ranges in size from 107-109, the result is deemed to be predictable with the library size being an obvious matter of choice. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 2, Wistar further teaches a 29-mer BRAF peptide incorporating the V600E mutation and the sequence EDLTVKIGDFGLATEKSRWSGSHQFEQLS (SEQ ID NO: 1) (see for example, paragraph 0005).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, and Huang et al. The artisan would have been motivated to make and use the invention as claimed because Wistar teaches means for raising synthetic, therapeutic antibodies against a cancer-specific neoepitope (see for example, the abstract, paragraphs 0005, 0090-0094 and 0120 and SEQ ID NO: 1 of Wistar) and Hacohen et al teach means of identifying personalized, cancer-specific, HLA-matched neoepitopes (see for example, the abstract, figure 1, and the caption of figure 1). Wistar further teaches the use of a 29-mer as a workable and successful size n-mer for a neoepitope against which a therapeutic, synthetic antibody may be predictably and successfully raised. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 3, Wistar further teaches that BRAF is an intracellular signaling protein expressed frequently in melanomas for which alleles were identified as somatic mutations in 70% of melanomas and a minority of other cancers including lung, colon and ovary carcinomas, but not in normal cells (citing Davies H, et al. Nature 2002; 417:949-54; Brose M S et al. Cancer Res 2002; 62:6997-7000; Pollock P M et al. Nat Genet. 2003; 33:19-20.-3 (see for example, paragraph 0004 of Wistar)). The BRAF mutations were located in exons 11 or 15, with BRAFV600E representing nearly all (92%) the BRAF alleles in melanoma (see for example, paragraph 0004). Therefore, the mutations are presumed to be relative to a normal (non-mutated BRAF), non-tumor sample which could presumably be taken from the same patient, meeting the limitations of instant claim 3. As mentioned above, Hacohen et al teach that the neoepitope is specific to the tumor and mutated (not present in normal tissue) relative to normal tissue.
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, and Huang et al. The artisan would have been motivated to make and use the invention as claimed because Wistar suggests and Hacohen et al teach that the neoepitope is mutated (not-present) in normal tissue, but is mutated (present) in tumor tissue (see for example, the abstract, paragraphs 0004, 0090-0094 and 0120 of Wistar; see additionally, for example, the abstract, figure 1, and the caption of figure 1 of Hacohen et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 7, note that the antibody against BRAFV600E may be an IgG antibody or a Fab construct (see for example, paragraphs 0091-0092 of Wistar).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, and Huang et al. The artisan would have been motivated to make and use the invention as claimed because Wistar teaches that this antibody format may be raised synthetically and may be used diagnostically or therapeutically (see for example, the abstract, paragraphs 0090-0094 and 0120 of Wistar). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 4 and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wistar in view of Hacohen et al and Huang et al, as applied to claims 1-3 and 7 above, and further in view of Tembhare et al (Quantification of expression of antigens targeted by antibody-based therapy in chronic lymphocytic leukemia. Am J Clin Pathol. 2013 Dec;140(6):813-8. doi: 10.1309/AJCPYFQ4XMGJD6TI) and Nagorsen et al (Cancer Immunol Immunother. 2008 Dec;57(12):1903-10. doi: 10.1007/s00262-008-0493-6. Epub 2008 Mar 4).
Wistar, Hacohen et al, and Huang et al teach the limitations of instant claims 1-3 and 7, as set forth above.
Regarding claim 4, as discussed above, Wistar teaches raising a synthetic, therapeutic antibody against a cancer-specific peptide comprising a mutation (a cancer neoepitope) and Hacohen et al further teach means to filtering neoepitopes for a cancer/tumor- and patient-specific neoepitope which is HLA-matched by predicted HLA-binding.
Hacohen et al further teach that tumors have been demonstrated to evade the immune system by limiting or shutting off expression of mutated neoantigens, but that tumors with multiple strongly immunogenic neoepitopes never escaped and cite to Castle et al who used de novo sequencing to identify tumor-specific mutations in the murine melanoma tumor and applied an algorithm to predict potential immunogenic epitopes generated by these mutations (see for example, paragraph 3 of the A case for neoantigens section of Hacohen et al).
Wistar, Hacohen et al, and Huang et al do not explicitly teach that the neoantigen is characterized by a strength of expression.
However, Tembhare et al teach that studies illustrate that the intensity of cell surface expression of target antigen by the leukemic cells may have an impact on the outcome of monoclonal antibody based treatment regimens (see for example, paragraph 2 of the Introduction). As the concept of "personalized medicine" gains popularity, discovery of a prognostic indicator of response to this type of therapy and more specifically which antibody based regimen is likely to be most effective in an individual patient is highly desirable (see for example, paragraph 2 of the Introduction). Pretreatment quantification of target antigen expression may aid in guiding patient management and choice of monoclonal antibody therapy, especially if levels of expression of targeted antigens vary significantly (see for example, paragraph 2 of the Introduction). Tembhare et al further quantified the levels of cell surface expression of CD20, CD22, CD25 and CD52 in CLL cells from patients and correlated them with each other as well as the absolute B-lymphocyte count at presentation (see for example, the second paragraph of the Introduction). The process of quantifying the expression strength of a target antigen is not described or supported to be distinct from the claimed filtering based on determined strength of expression of a neoepitope (understood the be the target antigen of the antibody; noting that expression strength is only mentioned twice in the specification (see for example, pages 3 and 7 of the instant specification).
Regarding the recitation that the neoepitope if filtered by a predetermined HLA-binding affinity, while Hacohen et al teach filtering by HLA-matching, they do not explicitly teach pre-determining a binding affinity towards an HLA-type.
However, Nagorsen et al teach that HLA-typing is particularly important because it is a prerequisite for successful specific immunotherapy. The HLA-specificity of antigen-derived peptide-epitopes is the basis for specific immunotherapy not only for cancer but also for viral infections (i.e., adoptive transfer of virus-specific T cells). HLA binding of antigen-derived epitopes is where immunotherapy begins. It has been shown that HLA affinity of a peptide can be more important for its immunogenicity than other mechanisms of the antigen-processing machinery (see for example, column 1 of page 1904).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, Nagorsen et al, and Tembhare et al. The artisan would have been motivated to make and use the invention as claimed because Tembhare et al teach that pretreatment quantification of target antigen expression may aid in guiding patient management and choice of monoclonal antibody therapy, especially if levels of expression of targeted antigens vary significantly (see for example, paragraph 2 of the Introduction), presumably to have a better chance of targeting the tumor and to decrease immune evasion by selecting a neoepitope less likely to be downregulated (as taught by Hacohen et al (see for example, paragraph 3 of the A case for neoantigens section). This teaching would guide the artisan to select for a neoantigen with a higher expression level (understood to be an expression strength in the absence of an alternative or preclusive definition) for greater success at targeting the tumor and decreasing immune evasion. The artisan would have been motivated to determine and filter the neoepitope by its predetermined HLA binding specificity as part of Hacohen et al’s HLA filtering in light of the cited teachings of Nargorsen et al to enhance the likelihood of selecting an immunologically active neoepitope. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 6, Wistar further teaches the use of a MHC class I (HLA) binding prediction score (held to read upon the limitation of HLA MHC class I matched epitope in light of paragraph 0034 of the instant specification used to provide insight into what is meant by said recitation) to filter/select for cancer neoepitopes (BRAFV600E) (see for example, paragraphs 0008, 0040, 0153 and Table 3 of Wistar).
Moreover, Hacohen et al teach patient-specific (personalized) cancer-specific (tumor-specific) neoepitopes (mutated peptides) are identified on the basis of predictive HLA-binding algorithms (see for example, the caption of figure 1).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, and Tembhare et al. The artisan would have been motivated to make and use the invention as claimed because Tembhare et al teach that pretreatment quantification of target antigen expression may aid in guiding patient management and choice of monoclonal antibody therapy, especially if levels of expression of targeted antigens vary significantly (see for example, paragraph 2 of the Introduction), presumably to have a better chance of targeting the tumor and to decrease immune evasion by selecting a neoepitope less likely to be downregulated (as taught by Hacohen et al (see for example, paragraph 3 of the A case for neoantigens section). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 8-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wistar, Hacohen et al, and Huang et al, as applied to claims 1-3 and 7 above, in further view of Chari et al (Antibody-drug conjugates: an emerging concept in cancer therapy. Angew Chem Int Ed Engl. 2014 Apr 7;53(15):3796-827. doi: 10.1002/anie.201307628. Epub 2014 Feb 20).
Wistar in view of Hacohen et al, and Huang et al teach the limitations of instant claims 1-3 and 7, as set forth above.
Regarding claims 8 and 9, Wistar further teaches use of the anti-BRAFV600E antibody, with or without other antibodies or chemotherapeutic agents [meeting the definition of a non-cellular agent, see for example, paragraph 0017 of the instant specification] (see for example, paragraphs 0120-0121 of Wistar).
Wistar, Hacohen et al, and Huang et al, et al do not teach that the antibody is conjugated to a chemotherapeutic (ADC).
However, Chari et al teach traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents (see for example, the abstract).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, and Chari et al. The artisan would have been motivated to make and use the invention as claimed because Chari et al teach the use of a targeting antibody (such as the antibody of Wistar) in an ADC to delivery cytotoxic moieties to reduce off-target toxicities observed in traditional cancer chemotherapy and to improve the therapeutic index of chemotherapeutic agents through enhancing selective-delivery (see for example, the abstract of Chari et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 10, Wistar in view of Hacohen et al, and Huang et al, do not explicitly teach that the chemotherapeutic is a drug.
However, Chari teaches the concept of antibody-drug conjugates (ADCs) showing the antibody conjugated to a drug moiety (which is cytotoxic/chemotherapeutic) (see for example, the abstract and graphical abstract of Chari et al). Chari et al additionally teach chemotherapy, or “treatment with chemicals” was the predominant modality for cancer treatment. Multidrug therapy became a standard modality for the treatment of most cancers. With such intensive chemotherapy, systemic toxicity to the host remains a major drawback of cytotoxic drugs in cancer treatment. In order to improve the therapeutic index of cancer drugs, either the potency of the cytotoxic agent had to be improved to lower the minimum effective dose (MED), or the tumor selectivity improved to increase the maximum tolerated dose (MTD) (see for example, Figure 1; see also, for example, the first paragraph of section 2. Targeted Therapies). An ideal solution would be the development of agents that would both decrease the MED and increase the MTD, thus increasing the overall therapeutic index of the cancer drug (see for example, the first 2 paragraphs of the Introduction). Chari et al proceed to teach that targeted therapy offers the potential to generate agents that will be selectively cytotoxic to tumor cells, coupled with lower toxicity to the host, resulting in a larger therapeutic index (see for example, the first paragraph of section 2. Targeted Therapies).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, and Chari et al. The artisan would have been motivated to make and use the invention as claimed because Chari et al teach that targeting the therapy to the cancer/tumor (such as by using the antibody made by the method of Wistar) increases the therapeutic index (see for example, the first paragraph of section 2. Targeted Therapies). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wistar, Hacohen et al, and Huang et al in view of Tembhare et al and Nagorsen et al as applied to claims 4 and 6 above, in further view of Qi et al (SEPPA 2.0—more refined server to predict spatial epitope considering species of immune host and subcellular localization of protein antigen, Nucleic Acids Research, Volume 42, Issue W1, 1 July 2014, Pages W59–W63, https://doi.org/10.1093/nar/gku395).
Wistar in view of Hacohen et al, Huang et al, and Tembhare et al teach the limitations of instant claims 4 and 6, as set forth above.
Regarding claim 5, note that the specification only mentions filtration by subcellular location twice and does not provide further detail(s) (see paragraphs 0011 and 0033 of the instant specification).
Wistar, Hacohen et al, Huang et al, and Tembhare et al do not explicitly teach filtering by subcellular location.
However, Qi et al teach a web interface Spatial Epitope Prediction server for Protein Antigens (SEPPA 2.0) which is a conformational epitope prediction algorithm. Qi et al teach that this algorithm has been improved by taking into account the subcellular location of the protein antigen (such as a neoepitope) (see for example, the abstract of Qi et al).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, Tembhare et al, and Qi et al. The artisan would have been motivated to make and use the invention as claimed because Qi et al teach that computational identification of immunogenic regions/segments in a given protein antigen has provided increasing assistance in guiding experimental validation (wherein their improved model which includes subcellular location filtering increased area under the curve (AUC) and decreased the number of false positives)(see for example, the abstract and the first 2 paragraphs of the Introduction of Qi et al). The MPEP provides that:
“The Supreme Court in KSR reaffirmed the familiar framework for determining obviousness as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), but stated that the Federal Circuit had erred by applying the teaching-suggestion-motivation (TSM) test in an overly rigid and formalistic way. KSR, 550 U.S. at 404, 82 USPQ2d at 1391. Specifically, the Supreme Court stated that the Federal Circuit had erred in four ways: (1) “by holding that courts and patent examiners should look only to the problem the patentee was trying to solve ” (Id. at 420, 82 USPQ2d at 1397); (2) by assuming “that a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem” (Id.); (3) by concluding “that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘obvious to try’” (Id. at 421, USPQ2d at 1397); and (4) by overemphasizing “the risk of courts and patent examiners falling prey to hindsight bias” and as a result applying “[r]igid preventative rules that deny factfinders recourse to common sense” (Id.). See also Novartis Pharms. Corp. v. West-Ward Pharms. Int'l Ltd., 923 F.3d 1051, 1059, 2019 USPQ2d 171676 (Fed. Cir. 2019); Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1047-48, 120 USPQ2d 1400, 1410 (Fed. Cir. 2016); and Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324, 1332, 102 USPQ2d 1445, 1449 (Fed. Cir. 2012)… Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Id. (2) “In Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., . . . [t]he two [pre-existing elements] in combination did no more than they would in separate, sequential operation.” Id. at 416-17, 82 USPQ2d at 1395. (3) “[I]n Sakraida v. AG Pro, Inc., the Court derived . . . the conclusion that when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” Id. at 417, 82 USPQ2d at 1395-96 (Internal quotations omitted.). The principles underlining these cases are instructive when the question is whether a patent application claiming the combination of elements of prior art would have been obvious. The Supreme Court further stated that:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. Id. at 417, 82 USPQ2d at 1396.
When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id,”
(see MPEP §2141(I)). The MPEP further provides that obviousness is demonstrated where the claimed invention would have been obvious to try (see MPEP §2143(I)(E)). Here, there was a known need in the art to develop better treatments for cancer, where tumor-specific epitopes have been a recent focus in research involving cancer therapeutics (see for example, paragraph 0002 of Wistar). As noted in the rejections of claims 1-3 and 4, above, the steps of filtering an epitope by measuring and selecting based upon n-mer size/length, strength of expression, HLA-matching, and, in view of Qi et al, subcellular location, were known in the art and represent a finite number of steps which may be combined in a finite number of sequences. The prior art combination cited teaches that the filters are helpful in selecting an epitope/neoepitope against which a synthetic antibody may be raised for cancer treatment/therapy, where adding in a filter for subcellular location further aids/enhances protein antigen (neoepitope) selection. While the claims do not specifically require any given order of filtering (such as n-mer, then strength, the HLA, and then subcellular location), any order of the filtering steps would have been obvious in light of the prior art for the artisan to try, noting that the elected invention is a composition, making the antibody, either a product or a product-by-process, in which case the process of making (including the process of neoepitope selection) is irrelevant to the question of novelty/nonobviousness where the prior art product makes obvious the product instantly claimed, absent a convincing and evidenced showing of an unexpected improvement resulting from the process by which the product is made. Here, no such improvement has been demonstrated. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 8, 11-12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wistar, Hacohen, and Huang et al, as applied to claims 1-3 and 7 above, in further view of view of Carter (Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1, 118–129 (2001). doi: 10.1038/35101072; as cited on the 03/13/2025 IDS).
Wistar in view of Hacohen et al, and Huang et al teach the limitations of instant claims 1-3 and 7, as set forth above.
Regarding claim 8, the combined references do not explicitly teach the composition of instant claim 1 wherein a therapeutic agent is coupled to the synthetic antibody.
However, Carter teaches that a variety of non-cellular therapeutic agents may be linked to an antibody for targeting the therapeutic agent to the cancer (see for example, the Key points bullet points at pages 1/51-2/51 and figure 1 and its caption).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, and Carter. The artisan would have been motivated to make and use the invention as claimed because Carter teaches that various anti-cancer moieties, such as a radionuclide or prodrug, may be linked to an antibody for pre-targeting to reduce systemic toxicities associated with radioimmunotherapy and cytotoxic chemotherapy, respectively (see for example, pages 19/51 21/51). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 11-12 and 14, Wistar in view of Hacohen et al, and Huang et al do not explicitly teach an effector cell as the additional therapeutic and/or the antibody bound to the genetically-mutated, high-affinity FcγRIII (CD16) of an NK cell.
However, Carter teaches that antibodies have been a common anti-cancer treatment, but that their efficacy has been limited because they are underpowered (see for example, paragraph 1 of the abstract at page 3/51, the paragraph bridging pages 3/51-4/51, and the second paragraph of page 4/51). Carter then teaches that antibodies may be paired with stronger anti-cancer therapeutics which addresses the low cytotoxicity of the antibody and enhances the cytotoxic moiety by targeting it to the tumor (see for example, the final key point bullet point on page 2/51, the paragraph bridging pages 4/51-5/51, Figures 1 and 2 and their respective captions and pages 5/51-6/51 and 9/51-10/51, the enhancing effector function section at pages 8/51-11/51, and the bispecific antibodies section at pages 18/51-19/51). Carter teaches that human antibodies, particularly IgG1 and IgG3, can potentially direct the killing of tumour cells by antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) (see for example, Figure 2 and its caption). Carter teaches natural killer (NK) cells have cytotoxic activity against tumor cells and that, when paired with a bispecific antibody, the NK cell may be targeted to tumor cells it would otherwise ignore (see for example, Figure 1 and the caption of figure 1b and pages 5/51-6/51, the enhancing effector functions section at pages 8/51-11/51, the bispecific antibodies section at pages 18/51-19/51, and Figure 2 and its caption at pages 9/51-10/51). Carter additionally teaches that ADCC is triggered by an interaction between the Fc region of an antibody that has bound, through its antigen-binding region, to a tumour cell and the Fcγ receptors (FcγRs), particularly FcγRI and FcγRIII, on immune effector cells such as neutrophils, macrophages and natural killer cells (see for example, paragraph 1 of the enhancing effector functions section at pages 8/51-9/51 and figure 2 and its caption at page 9/51). The tumour cell is eliminated by phagocytosis or lysis, depending on the type of mediating effector cell, thus treating the tumor (see for example, Figure 2 and its caption). Carter additionally teaches that bispecific antibodies that bind to a tumour-associated antigen and a so-called trigger antigen on an immune effector cell can recruit the effector cell to kill a tumour cell that it would otherwise disregard. The most extensively used trigger molecules are FcγRIII (CD16) on natural killer cells (see for example, paragraph 2 of the Bispecific Antibodies section on page 9/51-10/51). Carter further teaches that studies indicate the potential for increasing the antitumour activity of an antibody by manipulating the Fc region to increase its affinity for the activation receptor(s) and/or by abrogating its ability to bind to the inhibitory receptor.
While Carter does not explicitly teach that the NK cell is linked to an antibody against a neoantigen prior to any therapeutic use, Carter teaches that Fc-FcγR interactions are important for therapeutic cytotoxicity (ADCC) (see for example, paragraphs 2-3 of the Enhancing Effector Functions section on page 10/51 bridging 11/51 and Figure 2 and its caption). Carter further teaches that NK cells most commonly have a high-affinity CD16 FcγR which may bind to the Fc region of an IgG antibody. Carter appears to show this conformation (an effector cell bearing an FcγR bound to the Fc region of an antibody) wherein the antibody targets the effector cell to the tumor, therefore effecting therapeutic lysis (see for example, paragraphs 2-3 of the Enhancing Effector Functions section on page 10/51 bridging 11/51 and Figure 2 and its caption).
The MPEP provides that:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In reKerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In reCrockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parteQuadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious),”
(see MPEP section 2144.06(I)).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, and Carter. Here, it would have been obvious to a one of ordinary skill in the art to combine an antibody for targeting cancer, such as the therapeutic, synthetic, IgG antibody of Wistar with a therapeutic effector cell, such as the NK cell bearing a high affinity CD16 of Carter. The artisan would have been motivated to make and use the invention as claimed because Carter teaches that these components can be used individually to treat cancer and that they can be used, at least, in tandem to treat cancer (see for example, paragraph 1 of the abstract at page 3/51, the paragraph bridging pages 3/51-4/51, the second paragraph of page 4/51, the enhancing effector functions section at pages 8/51-11/51, the bispecific antibodies section at pages 18/51-19/51, and Figure 2 and its caption at pages 9/51-10/51). One of ordinary skill in the art would have found it obvious to attach the antibody of Wistar to the NK cell as taught by Carter (attaching the Fc of the antibody to the CD16 (FcγR) of the NK cell as shown and described by the cited teachings of Carter)(see for example, fig 2 and its caption). One of ordinary skill in the art would have been motivated to use the resulting composition to treat cancer because Carter teaches this is a targeted and effective treatment for effecting tumor lysis or phagocytosis (treatment)(see for example, figure 2 and its caption at pages 9/51-10/51). There are 2, finite options for attachment of the IgG Fc to the CD16 of the NK cell, before or after administration. The artisan, looking to meet the long felt need of treating cancer would have wanted to take advantage of the enhanced ADCC and targeting taught by Carter and would have found it obvious to try to connect the Fc of the IgG antibody, such as that of Wistar, to the high-affinity CD16 commonly possessed by an NK cell allowing for attachment to said Fc region (see MPEP §2143(I)(E)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 8 and 11-13 is/are alternatively rejected under 35 U.S.C. 103 as being unpatentable over Wistar, Hacohen et al, and Huang et al, as applied to claims 1-3 and 7 above, in further view of view of Shi et al (Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects. Mol Cancer. 2014 Sep 21;13:219. doi: 10.1186/1476-4598-13-219).
The combined references teach the limitations of instant claims 1-3 and 7, as set forth above.
Regarding claims 8 and 11-13, Wistar teaches an IgG antibody against a cancer neoepitope, as discussed above.
Wistar in view of Hacohen et al, and Huang et al do not explicitly teach an effector cell as the additional therapeutic and/or that the T-cell has an scFv ectodomain with a genetically modified CD16 receptor.
However, Shi et al teach that to expand the applications for T cell-based immunotherapy in cancer, researchers have constructed similar “universal” CARs (uCAR) that utilize anti-fluorescein isothiocyanate (FITC) scFv (see for example, Figure 1C and its caption). These uCAR T cells recognize various cancer types when bound to FITC-labeled or biotinylated antigen-specific mAbs or scFvs, resulting in efficient target lysis, T-cell proliferation, and cytokine production, effectively treating the tumor. Shi et al teach that more recently, Kudo et al constructed a novel uCAR containing the high-affinity CD16 (FCGR3A) V158 variant (a genetically modified CD16). CD16V-based uCAR T cells have bound humanized antibodies with higher affinity and engagement of the CD16V-uCAR provoked T cell activation, exocytosis of the lytic granules and sustained proliferation, thereby enhancing the therapeutic effects of the T cell-based anti-tumor therapy. Further, the co-administration of CD16V uCAR T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo (see for example, the CAR binding domain section).
It would have been prima facie before the effective filing date of the invention obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, Huang et al, Shi et al. The artisan would have been motivated to make and use the invention as claimed because Shi et al teach that a uCAR T-cell having a genetically modified CD16V may be paired with an scFv (in the ectodomain) which aids in targeting the uCAR T-cell to the tumor tissue where the modified CD16 then enhances the antitumor effects (for example, lysis) of the T-cell for tumor treatment (see for example, Figure 1 and its caption and CAR binding domain section of Shi et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Maintained-Double Patenting
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 1-3, 8, and 11-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 17/740,040 (reference A) in view of Wistar and Huang et al as applied to the claims in the rejections under 35 USC 103 and the rejection of claim 1 for non-statutory double patenting above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
This is a provisional nonstatutory double patenting rejection.
Note that the teachings/claimed matter cited and arguments as applied in the rejections of claim1 for double patenting over reference A are incorporated herein.
Regarding claim 1, reference A claims an composition comprising a carrier with or coupled to a synthetic antibody that binds to a cancer driver neoepitope (see reference A claim 1). The neoepitope may be patient specific (see claim 7 of reference A). The neoepitope may also be HLA-matched (see claim 13 of reference A). The neoepitope may also be expressed in the solid tumor tissue (held to read upon the instant recitation of being cancer-specific).
Reference A does not teach that the antibody has grafted CDRs into a scaffold (i.e. that the antibody is humanized or chimeric) or that that antibody is bound to the neoepitope which is immobilized on a solid support.
However, Wistar teaches the process of using BRAF peptides, such as the mutated BRAF 29-mer having the V600E mutation (neoepitopes), for use in screening antibodies from libraries of antibodies to isolate antibodies that bind the neoepitope(s) (see for example, paragraphs 0004-0006, 0091-0092, and 0124-0125). Wistar further teaches that conventional drug screening techniques may be employed using the peptides described herein. As one example, a method for identifying compounds which specifically bind to a peptide include the steps of contacting a selected peptide with a test compound to permit binding of the test compound to the peptide; and determining the amount of test compound, if any, which is bound to the peptide. Such a method may involve the incubation of the test compound and the peptide immobilized on a solid support (see for example, paragraph 0126).
Reference A and Wistar do not teach that the grafted CDRs are selected from a high-diversity library.
However, Huang et al teach that phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens. The size and quality of libraries are crucial for the success of phage display. Currently, methods for the production of peptide libraries can lead to library sizes from 109 to 1011, with the average library generally containing 107 members. Optimized and novel strategies to generate large antibody libraries have been carried out, increasing the diversity to 1012, noting that M13 phage library display technology is well-known in the art (see for example, pages 4569-4751). Huang et al teach that advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens (see for example, page 4569 at the abstract and pages 4571-4573).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Wistar, and Huang et al. The artisan would have been motivated to make and use the invention as claimed because Wistar teaches means for raising synthetic, therapeutic antibodies against a cancer-specific neoepitope (see for example, the abstract, paragraphs 0090-0094 and 0120 of Wistar), using a library and screening such that the neoepitope is immobilized on a support. Where Wistar teaches the use of humanized antibodies, the artisan would have found it obvious to take CDRs from the screened library and graft them into a human antibody framework (a scaffold as is consistent with page 17 of the instant specification). Upon further screening to confirm continued specificity, the synthetic antibody having grafted CDRs from the high-diversity library of Wistar as modified by Huang et al in a human scaffold would have been bound to the neoepitope of Wistar as modified by reference A, said neoepitope being immobilized on a solid support (prior to isolation of the neoepitope-binding antibody). Using the process of Wistar for antibody generation, the artisan would have understood the desirability of selecting a neoepitope that is that is personalized (patient-specific), cancer-specific, and HLA-matched through the means taught by reference A (as cited above). The artisan would have further found it obvious, to modify the library used in Wistar to be a high-diversity library in order to allow for better generation and screening of antibodies as taught by Huang et al (noting that even the average phage library generated by traditional means comprises 107 members while many technologies yield library sizes from 109 or more, with larger sized being desirable, noting that optimized techniques yield libraries with 1012 members). Where the library ranges in size from 107-109, the result is deemed to be predictable with the library size being an obvious matter of choice. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 2, reference A claims that the neoepitope may be 7-20 amino acids in length making obvious that some neoepitopes will be that n-mer length (see claim 12 of reference A).
Regarding claim 3, reference A claims that the neoepitope is patient and cancer/tumor-specific and is an expressed missense (characterized by/comprises a mutation as instantly recited) (see claim 11 of reference A).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Huang et al, and Wistar. The artisan would have been motivated to make and use the invention as claimed because reference A claims an antibody defined by the same limitation (of the same scope) (see claims 1, 7, and 11-13 of reference A; see further for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 8 and 11-12, as discussed above, reference A claims a synthetic antibody which may be coupled to a carrier. Reference A further claims that this carrier may be an immune competent cell (see claim 3 of reference A), which may be a CD8+ T cell or an NK cell (see claim 4 of reference A). Note that the immune competent cell of reference A is encompassed within the instant recitation of a therapeutic agent (see for example, instant claim 11).
Claims 4 and 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 17/740,040 (reference A) in view of Wistar, Huang et al, Hacohen et al, Nagorsen et al, and Tembhare et al, as cited in the rejections under 35 USC 103 and the rejections of claims 1-3 for non-statutory double patenting above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
This is a provisional nonstatutory double patenting rejection.
Note that the teachings/claimed matter cited and arguments as applied in the rejections of claims 1-3 for double patenting over reference A and Huang et al are incorporated herein.
Regarding claim 4, reference A does not teach that the neoepitope is characterized by having a mutation type, strength of expression, and by a predetermined binding affinity towards the HLA-type of the patient. However, Wistar, Huang et al, Hacohen et al, and Tembhare et al make obvious such means of characterization of the neoepitope (as discussed in the rejections of the claims under 35 USC §103; see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). Moreover, any neoepitope is characterized by the traits because it has some value related to them just by existing as a composition where no further detail is provided to preclude such interpretation. However, Nagorsen et al teach that HLA-typing is particularly important because it is a prerequisite for successful specific immunotherapy. The HLA-specificity of antigen-derived peptide-epitopes is the basis for specific immunotherapy not only for cancer but also for viral infections (i.e., adoptive transfer of virus-specific T cells). HLA binding of antigen-derived epitopes is where immunotherapy begins. It has been shown that HLA affinity of a peptide can be more important for its immunogenicity than other mechanisms of the antigen-processing machinery (see for example, column 1 of page 1904).
Therefore, reference A in view of Wistar, Huang et al, Hacohen et al, Nagorsen et al, and Tembhare et al are held to make obvious instant claim 4.
Regarding claim 6, reference A, Wistar, Huang et al, Hacohen et al, Nagorsen et al, and Tembhare et al further make obvious matching the HLA-matched neoepitope for MHC-I presentation, as discussed above in the rejections of the claims under 35 USC §103 (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al).
Regarding claim 7, reference A, Wistar, Huang et al, Hacohen et al, Nagorsen et al, and Tembhare et al further make obvious at least the use of an IgG antibody format or a Fab fragment, as discussed above in the rejections of the claims under 35 USC §103 (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Wistar, Huang et al, Hacohen et al, and Tembhare et al. The artisan would have been motivated to make and use the invention as claimed because reference A claims an antibody defined by the same limitation (of the same scope) (see claims 1, 7, and 13 of reference A). Wistar further defines the synthetic antibody and Wistar in view of Hacohen et al and Tembhare et al further teach the recited limitations regarding the selection of the neoepitope (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/740,040 (reference A) in view of Wistar, Huang et al, Hacohen et al, Tembhare et al, and Carter as applied to the claims in the rejections under 35 USC 103 above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
This is a provisional nonstatutory double patenting rejection.
Note that the teachings/claimed matter cited and arguments as applied in the rejections of claim 1-4, 6-8, and 11-12 for double patenting over reference A in view Wistar, Huang et al, Hacohen et al, and Tembhare et al are incorporated herein.
Regarding claim 14, reference A claims that the cell may be an NK cell (see claim 4 of reference A). The cell may be recombinant and comprise a CAR having binding specificity for a patient-specific cancer driver neoepitope (see reference A claims 19-20). Reference a further claims an scFv which binds a cancer neoepitope (see claim 1 of reference A). Reference A does not explicitly claim an NK cell comprising an IgG antibody against a cancer neoepitope as instantly claimed wherein the cell further comprises a genetically modified CD16 receptor (FcγIIIR). However, Carter teaches that human antibodies, particularly IgG1 and IgG3, can potentially direct the killing of tumour cells by antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). ADCC is triggered by an interaction between the Fc region of an antibody that has bound, through its antigen-binding region, to a tumour cell and the Fcγ receptors (FcγRs), particularly FcγRI and FcγRIII, on immune effector cells such as neutrophils, macrophages and natural killer cells. The tumour cell is eliminated by phagocytosis or lysis, depending on the type of mediating effector cell (see for example, Fig 2 of Carter). Carter additionally teaches that bispecific antibodies that bind to a tumour-associated antigen and a so-called trigger antigen on an immune effector cell can recruit the effector cell to kill a tumour cell that it would otherwise disregard. The most extensively used trigger molecules are FcγRIII (CD16) on natural killer cells (see for example, paragraph 2 of the Bispecific Antibodies section). Carter further teaches that studies indicate the potential for increasing the antitumour activity of an antibody by manipulating the Fc region to increase its affinity for the activation receptor(s) and/or by abrogating its ability to bind to the inhibitory receptor. Indeed, point mutations in the Fc region, which result in improved binding to FcγRIII, yielded up to a twofold enhancement in ADCC in vitro (see for example, paragraph 3 of the Enhancing Effector Functions section). Therefore, the resulting FcγIIIR (CD16) is presumed to be genetically modified and to have a high affinity as instantly recited (there being no clear structural distinction between the FcγIIIR (CD16) made obvious by the prior art and that encompassed by the instant claims as drafted).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Wistar, Huang et al, Hacohen et al, and Tembhare et al, and Carter. The artisan would have been motivated to make and use the invention as claimed because reference A claims an antibody defined by the same limitation (of the same scope) (see claims 1, 7, and 13 of reference A). Wistar further defines the synthetic antibody and Wistar in view of Hacohen et al and Tembhare et al further teach the recited limitations regarding the selection of the neoepitope (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). Carter then teaches that antibodies and NK cells are effective individually for treating cancer and that antibodies may be used to target NK cells by attaching the antibody Fc to the FcγR (CD16) of the NK cell to target the NK cell to tumor cells it may otherwise ignore (further note that it is prima facie obvious to combine 2 compositions for accomplishing a shared purpose known in the prior art (see MPEP §2144.06(I)); see also for example, the Key points bullet points at pages 1/51-2/51 and figure 1 and its caption, paragraph 1 of the abstract at page 3/51, the pages 3/51-11/51, and pages 18/51-19/51 of Carter). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 9-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 17/740,040 (reference A) in view of Wistar, Huang et al, Hacohen et al, Tembhare et al, and Chari et al as applied to the claims in the rejections under 35 USC 103 above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
This is a provisional nonstatutory double patenting rejection.
Note that the teachings/claimed matter cited and arguments as applied in the rejections of claim 4, 6-8, and 11 for double patenting over reference A in view of Wistar, Huang et al, Hacohen et al, and Tembhare et al are incorporated herein.
Regarding claim 9, neither Reference A, Huang et al, Tembhare et al, or Wistar claim or teach explicitly that the antibody is conjugated to a chemotherapeutic (ADC). However, Chari et al teach traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. Therefore, one of ordinary skill in the art looking to treat cancer would have found it obvious to use a targeted antibody, such as the synthetic antibody of reference A and Wistar, conjugated to a cytotoxic/chemotherapeutic moiety in order to effectively treat the tumor while decreasing off target effects.
Regarding claim 10, Wistar does not explicitly teach that the chemotherapeutic is a drug. However, Chari teaches the concept of antibody-drug conjugates (ADCs) showing the antibody conjugate to a drug moiety (which is cytotoxic/chemotherapeutic). Therefore, one of ordinary skill in the art looking to apply the teachings of Wistar to treat cancer would have found it obvious to modify the teachings of Wistar as taught by Chari et al in order to provide effective and targeted treatment to the tumor using an ADC comprising the antibody of Reference A and Wistar and a chemotherapeutic drug of Chari et al and Wistar as modified by Hacohen et al, Huang et al, and Tembhare et al.
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Huang et al, Wistar, Hacohen et al, and Tembhare et al, and Carter. The artisan would have been motivated to make and use the invention as claimed because reference A claims an antibody defined by the same limitation (of the same scope) (see claims 1, 7, and 13 of reference A). Wistar further defines the synthetic antibody and Wistar in view of Hacohen et al and Tembhare et al further teach the recited limitations regarding the selection of the neoepitope (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). Chari et al then teach the desirability of paring an antibody targeting cancer to a cytotoxic moiety to form an ADC for treating cancer (see for example, abstract and graphical abstract, Figure 1, the first paragraph of section 2. Targeted Therapies, and first 2 paragraphs of the Introduction of Chari et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 17/740,040 (reference A) in view of Wistar, Huang et al, Hacohen et al, Tembhare et al, Nargorsen et al, and Qi et al as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
This is a provisional nonstatutory double patenting rejection.
Note that the teachings/claimed matter cited and arguments as applied in the rejections of claim 1-4, 8, and 11 for double patenting over reference A in view of the combined supporting references are incorporated herein.
Regarding claim 5, note that the specification only mentions filtration by subcellular location twice and does not provide further detail (see paragraphs 0011 and 0033 of the instant specification). However, Qi et al teach a web interface Spatial Epitope Prediction server for Protein Antigens (SEPPA 2.0) which is a conformational epitope prediction algorithm. Qi et al teach that this algorithm has been improved by taking into account the subcellular location of the protein antigen (such as a neoepitope) (see for example, the abstract of Qi et al). As noted above, the steps of filtering an epitope by measuring and selecting based upon n-mer size/length, strength of expression, HLA-matching, and, in view of Qi et al, subcellular location, were known in the art and represent a finite number of steps which may be combined in a finite number of sequences. The prior art combination cited teaches that the filters are helpful in selecting an epitope/neoepitope against which a synthetic antibody may be raised for cancer treatment/therapy, where adding in a filter for subcellular location further aids/enhances protein antigen (neoepitope) selection. While the claims do not specifically require any given order of filtering (such as n-mer, then strength, the HLA, and then subcellular location), any order of the filtering steps would have been obvious in light of the prior art for the artisan to try, noting that the elected invention is a composition, making the antibody, either a product or a product-by-process, in which case the process of making (including the process of neoepitope selection) is irrelevant to the question of novelty/nonobviousness where the prior art product makes obvious the product instantly claimed, absent a convincing and evidenced showing of an unexpected improvement resulting from the process by which the product is made. Here, no such improvement has been demonstrated.
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Wistar, Huang et al, Hacohen et al, Nagorsen et al, Tembhare et al, and Qi et al. The artisan would have been motivated to make and use the invention as claimed because Qi et al teach that computational identification of immunogenic regions/segments in a given protein antigen has provided increasing assistance in guiding the experimental validation (wherein their improved model which includes subcellular location filtering increased area under the curve (AUC) and decreased the number of false positives) (see for example, the abstract and the first 2 paragraphs of the Introduction of Qi et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 1-5 and 7-10 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11421016 B2 (reference B). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims teach the process resulting in a product encompassed within the instant claims.
Regarding claims 1, 4-5, and 8, Reference B claims:
“A method of generating a pharmaceutical agent for cancer immune therapy, comprising:
using matched normal omics data of a tumor to generate in silico a plurality of n-mers that contain at least one patient- and cancer-specific cancer neoepitope wherein the omics data from each of the tumor and the matched patient normal sample include data selected from the group consisting of whole genomic sequencing data, exome sequencing data, transcriptome data, and combinations thereof;
filtering in silico the n-mers to so obtain a subset of neoepitope sequences wherein the filtering is filtering by type of mutation, filtering by strength of expression, filtering by subcellular location [as recited in instant claim 5], and/or filtering by binding affinity towards an HLA-type of the patient [as recited in instant claim 4];
preparing at least one synthetic n-mer peptide using sequence information from the subset of neoepitope sequences;
using the synthetic n-mer peptide to isolate a recombinant antibody;
obtaining sequence information of the complementarity determining region of the recombinant antibody;
generating a synthetic antibody using the sequence information of the complementarity determining region of the recombinant antibody; and
coupling the synthetic antibody to a therapeutic or diagnostic agent to so obtain the pharmaceutical agent[as recited in instant claim 8],”
(see claim 1 of reference B; underlined portions added to highlight text of particular interest).
The copending reference application does not appear to explicitly claim the use of a high-diversity library to arrive at CDRs which are then grafted into a scaffold (such as a known framework to result in an antibody that is humanized or chimeric) where the antibody is bound to the neoepitope which is immobilized on a solid support.
However, the specification can be used to determine the utility of a product. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1385 (CAFC 2010) (“Our prior obviousness-type double patenting decisions in Geneva and Pfizer … we found claims of a later patent invalid for obviousness-type double patenting where an earlier patent claimed a compound, disclosing its utility in the specification, and a later patent claimed a method of using the compound for a use described in the specification of the earlier patent”). See also MPEP § 804(II)(B)(2)(a).
The specification of the copending reference application teaches that an object of its disclosure is identification and use of neoepitopes in the production of neoepitope specific antibodies and the use of said neoepitopes and antibodies in prophylaxis and therapy (see for example, column 1 at lines 10-16 of the specification of reference B). Means of said identification taught by the specification of reference B include the use of a high-diversity library and phage display having a diversity of at least 109 diverse members or greater (see for example, columns 3, 5, and 12 of the specification of reference B) where CDR/SDRs may be grafted onto a scaffold (see for example, columns 2-3 of the specification of reference B) where the synthetic peptide (neoepitope) may be immobilized on a solid phase/support allowing for isolation of antibodies to the neoepitope (see for example, column 12 of the specification of reference B).
As noted above, the steps of filtering an epitope by measuring and selecting based upon n-mer size/length, strength of expression, HLA-matching, and, subcellular location, were known in the art and represent a finite number of steps which may be combined in a finite number of sequences. The prior art combination cited teaches that the filters are helpful in selecting an epitope/neoepitope against which a synthetic antibody may be raised for cancer treatment/therapy, where adding in a filter for subcellular location further aids/enhances protein antigen (neoepitope) selection. While the claims do not specifically require any given order of filtering (such as n-mer, then strength, the HLA, and then subcellular location), any order of the filtering steps would have been obvious in light of the prior art for the artisan to try, noting that the elected invention is a composition, making the antibody, either a product or a product-by-process, in which case the process of making (including the process of neoepitope selection) is irrelevant to the question of novelty/nonobviousness where the prior art product makes obvious the product instantly claimed, absent a convincing and evidenced showing of an unexpected improvement resulting from the process by which the product is made. Here, no such improvement has been demonstrated.
Therefore, the artisan would have found it prima facie obvious before the effective filing date of the invention to use the antibody moiety comprising the instantly claimed sequences (alone, as a fragment, or as a bispecific/multispecific) to treat a human disease, such as cancer. Therefore, reference B claims a synthetic antibody against a cancer and patient-specific, HLA-matched neoepitope, meeting the limitations of instant claim 1.
Regarding claim 2, Reference B claims n-mer (neoepitope) peptides of 7-11 amino acids in length, meeting the limitations of instant claim 2 (see claim 3 of reference B).
Regarding instant claim 3, claims 1 and 6 of reference B claim neoepitope filtering by mutation type where presumably the mutation is relative to a normal tissue (supported by paragraph 3 of the detailed description section of reference B, sought out to clarify the recitations of mutation filtering).
Regarding claim 7, reference B claims that the synthetic antibody is generated via recombinant expression as a IgG, a F(ab′)2, a Fab′, a Fab, or a scFv (see claim 11 of reference B).
Regarding claims 9-10, reference B claims that the therapeutic or diagnostic agent is non-cellular and may be a chemotherapeutic drug, a radio isotope, a PET detectable isotope, a SPECT detectable isotope, or an affinity agent (see claims 12-13 of reference B).
Regarding claims reference B claims that the therapeutic agent may be a cell such as a T-cell or NK cell and may be a T cell expressing a CAR wherein the scFv is the synthetic antibody and wherein the scFv is in the ectodomain (see claims 14-16 of Reference B). Reference B also claims that the therapeutic agent may be a cell such as an NK cell and may be an NK cell expressing a high-affinity Fcγ (CD16) and wherein the antibody is a synthetic IgG bound to the NK cell via the Fcγ receptor (see claim 17 of reference B).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosure of reference B. The artisan would have been motivated to make and use the invention as claimed because reference B claims an antibody and neoepitope that the antibody binds defined by the same limitations (of the same scope) (see claims 1, 3, 6, and 11-17 of reference B). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 1-3 and 8-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of US Patent No. 12404490 (formerly cited as copending Application No. 17/938,270; herein after referred to as ‘reference C’) in view of Huang et al, Wistar, and Hacohen et al as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Regarding claim 1, reference C claims a method of producing an antibody and directing the antibody to a cancer cell expressing a neoepitope (such that the antibody is deemed to read upon producing an antibody which binds a cancer neoepitope) (see claim 1 of reference C).
Reference C does not teach that the CDRs are derived from a high-diversity library and grated into a scaffold.
However, Huang et al teach that phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens. The size and quality of libraries are crucial for the success of phage display. Currently, methods for the production of peptide libraries can lead to library sizes from 109 to 1011, with the average library generally containing 107 members. Optimized and novel strategies to generate large antibody libraries have been carried out, increasing the diversity to 1012, noting that M13 phage library display technology is well-known in the art (see for example, pages 4569-4751). Huang et al teach that advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens (see for example, page 4569 at the abstract and pages 4571-4573).
Reference C and Huang et al do not claim that the neoepitope is patient-specific of cancer specific or HLA-matched or filtered for a mutation.
However, Wistar and Hacohen et al teach means of producing such a synthetic antibody against an neoepitope and further teach the benefits of the involved filtering steps for the resulting antibody product, which may be humanized or chimeric and may be screened by immobilizing the neoepitope on a solid phase support such that the antibody is bound to the immobilized neoepitope (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 124-126, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al), making obvious the production of such a product (the antibody of reference C using the method of Wistar as modified by Huang et al and Hacohen et al) with a reasonable expectation of success. Where the library ranges in size from 107-109, the result is deemed to be predictable with the library size being an obvious matter of choice. Therefore, the claim would have been obvious before the filing date of the invention, with a reasonable expectation of success in light of the cited teachings as combined herein.
Regarding claim 2, reference C does not teach the n-mer size of the neoepitope. However Wistar teaches the use of an n-mer of 29 amino acids (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar, as discussed above in the rejections under 35 USC §103), making obvious with a reasonable expectation of success selection of an n-mer within the instantly recited range.
Regarding claim 3, reference C does not teach that the neoepitope has a mutation not present in normal tissue. However Wistar teaches the that the neoepitope has a mutation and Hacohen et al teach that the neoepitope has a mutation/is present as a mutated sequence in tumor tissue and not in normal tissue (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference C, Wistar, Huang et al, and Hacohen et al. The artisan would have been motivated to make and use the invention as claimed because reference C claims an antibody and neoepitope defined by the same limitations (of the same scope) (see claim 1 of reference C; see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 8-11, reference C claims an antibody binding a neoepitope (see claim 17 of reference C) wherein the antibody comprises a therapeutic agent which may be a chemotherapeutic drug, a radiologic agent, or chimeric T-cell receptor of a cytotoxic T cell or an NK cell (see claims 4-5, 7-9 and 19 of reference C).
Claims 4 and 6-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of US Patent No. 12404490 (formerly cited as copending Application No. 17/938,270; herein after referred to as ‘reference C’) in view of Wistar, Huang et al, Hacohen et al, Nagorsen et al, and Tembhare et al as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 1-3 for double patenting with respect to reference C in view of Wistar, Huang et al, and Hacohen et al, above, are incorporated herein.
Regarding claim 4, reference C does not teach that the neoepitope is characterized by having a mutation type, strength of expression, and by a predetermined binding affinity towards the HLA-type of the patient. However, Wistar, Huang et al, Hacohen et al, and Tembhare et al make obvious such means of characterization of the neoepitope as means for selecting a therapeutically significant neoepitope with better quality metrics (such as increased AUC and fewer false positives as discussed in the rejections under 35 USC 103, above; see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). Nagorsen et al teach that HLA-typing is particularly important because it is a prerequisite for successful specific immunotherapy. The HLA-specificity of antigen-derived peptide-epitopes is the basis for specific immunotherapy not only for cancer but also for viral infections (i.e., adoptive transfer of virus-specific T cells). HLA binding of antigen-derived epitopes is where immunotherapy begins. It has been shown that HLA affinity of a peptide can be more important for its immunogenicity than other mechanisms of the antigen-processing machinery (see for example, column 1 of page 1904).
Regarding claim 6, Wistar, Huang et al, Hacohen et al, and Tembhare et al further make obvious matching the HLA-matched neoepitope for MHC-I presentation, as discussed above in the rejections of the claims under 35 USC §103 (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al).
Regarding claim 7, Wistar, Huang et al, Hacohen et al, and Tembhare et al further make obvious at least the use of an IgG antibody format or a Fab fragment, as discussed above in the rejections of the claims under 35 USC §103 (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al).
Claims 12 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of US Patent No. 12404490 (formerly cited as copending Application No. 17/938,270; herein after referred to as ‘reference C’) in view of Wistar, Huang et al, Hacohen et al, Tembhare et al, and Carter as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 1-3 and 8-11 for double patenting with respect to reference C in view of Wistar, Huang et al, and Hacohen et al, are incorporated herein.
Regarding claims 12 and 14, reference C does not teach the use of a genetically modified CD16 (FcγIIIR). However, Carter teaches that antibodies and NK cells are known individually to treat cancer. Carter teaches that antibodies may be paired with an NK cell, through attachment of the Fc to the FcγR (high-affinity CD16) of the NK cell to target the NK cell to tumor cells it may otherwise ignore.
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference C, Wistar, Huang et al, Hacohen et al, and Carter. The artisan would have been motivated to make and use the invention as claimed because reference A claims an antibody defined by the same limitation (of the same scope) (see claims 1, 4-5, 7-9, and 19 of reference C). Wistar further defines the synthetic antibody and Wistar in view of Hacohen et al and Tembhare et al further teach the recited limitations regarding the selection of the neoepitope (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). Carter then teaches that antibodies and NK cells are effective individually for treating cancer and that antibodies may be used to target NK cells by attaching the antibody Fc to the FcγR (CD16) of the NK cell to target the NK cell to tumor cells it may otherwise ignore (further note that it is prima facie obvious to combine 2 compositions for accomplishing a shared purpose known in the prior art (see MPEP §2144.06(I)).; see also for example, the Key points bullet points at pages 1/51-2/51 and figure 1 and its caption, paragraph 1 of the abstract at page 3/51, the pages 3/51-11/51, and pages 18/51-19/51 of Carter). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 13 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of US Patent No. 12404490 (formerly cited as copending Application No. 17/938,270; herein after referred to as ‘reference C’) in view of Wistar, Huang et al, and Hacohen et al, and Shi et al as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 1-3 and 8-12 for double patenting with respect to reference C in view of Wistar, Huang et al, and Hacohen et al above, are incorporated herein.
Regarding claim 13, as noted above, the combined references make obvious the limitations of claim 12. Reference C does not claim the antibody is an scFv in the ectodomain of a CAR T-cell. However, Shi et al teach the utility and format of a CAR T-cell with an scFv in the ectodomain further comprising a genetically modified CD16 (see additionally for example, Figure 1C and its caption and the CAR binding domain section of Shi et al).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference C, Wistar, Huang et al, Hacohen et al, Tembhare et al, and Shi et al. The artisan would have been motivated to make and use the invention as claimed because reference A claims an antibody defined by the same limitation (of the same scope) (see claims 1, 4-5, 7-9, and 19 of reference C). Wistar, Huang et al, Hacohen et al, and Tembhare et al describe the desirability and predictability of using a neoepitope meeting the instantly claimed limitations (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). Shi et al then teaches the desirability of using an antibody/scFv to target a T cell comprising a CD16 (see for example, Figure 1C and its caption and the CAR binding domain section of Shi et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of US Patent No. 12404490 (formerly cited as copending Application No. 17/938,270; herein after referred to as ‘reference C’) in view of Wistar, Huang et al, Hacohen et al, Tembhare et al, Nagorsen et al, and Qi et al as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 1-4 and 6-11 for double patenting with respect to reference C in view of Wistar, Huang et al, Hacohen et al, and Tembhare et al above, are incorporated herein.
Regarding claim 5, as noted above, the combined references teach the limitations of claim 4. Reference C does not claim the neoepitope is filtered by a subcellular location. However, Qi et al teach a web interface Spatial Epitope Prediction server for Protein Antigens (SEPPA 2.0) which is a conformational epitope prediction algorithm. Qi et al teach that this algorithm has been improved by taking into account the subcellular location of the protein antigen (such as a neoepitope) (see for example, the abstract of Qi et al). As noted above, the steps of filtering an epitope by measuring and selecting based upon n-mer size/length, strength of expression, HLA-matching, and, in view of Qi et al, subcellular location, were known in the art and represent a finite number of steps which may be combined in a finite number of sequences. The prior art combination cited teaches that the filters are helpful in selecting an epitope/neoepitope against which a synthetic antibody may be raised for cancer treatment/therapy, where adding in a filter for subcellular location further aids/enhances protein antigen (neoepitope) selection. While the claims do not specifically require any given order of filtering (such as n-mer, then strength, the HLA, and then subcellular location), any order of the filtering steps would have been obvious in light of the prior art for the artisan to try, noting that the elected invention is a composition, making the antibody, either a product or a product-by-process, in which case the process of making (including the process of neoepitope selection) is irrelevant to the question of novelty/nonobviousness where the prior art product makes obvious the product instantly claimed, absent a convincing and evidenced showing of an unexpected improvement resulting from the process by which the product is made. Here, no such improvement has been demonstrated.
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference C, Wistar, Huang et al, Hacohen et al, Tembhare et al, and Qi et al. The artisan would have been motivated to make and use the invention as claimed because Qi et al teach that computational identification of immunogenic regions/segments in a given protein antigen has provided increasing assistance in guiding the experimental validation (wherein their improved model which includes subcellular location filtering increased area under the curve (AUC) and decreased the number of false positives)(see for example, the abstract and the first 2 paragraphs of the Introduction of Qi et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 1-3 and 8-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/057,588 (reference D) in view of Wistar, Huang et al, and Hacohen et al as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, reference D claims a method of targeting a cancer cell expressing a neoepitope comprising contacting the cancer cell with an antibody that binds the neoepitope expressed on the cancer cell, wherein the antibody may be synthetic (see claims 1 and 11 of reference D). Wistar also teaches the use and production of a synthetic antibody raised against a neoantigen (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar).
Reference D does not teach that the neoepitope is patient-specific and HLA-matched.
However, Hacohen et al teach means for filtering a neoepitope by sampling normal and tumor tissue to select a neoepitope (mutated peptide) that is cancer-specific, patient-specific, and HLA-matched (see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al).
Reference D and Hacohen et al do not teach that the antibody has grafted CDRs from a high-diversity library or that the antibody is bound to the neoepitope, when the neoepitope is immobilized on a solid phase support.
However, Wistar teaches antibodies (which may be therapeutic or diagnostic) (reading on a composition comprising antibodies as no other limitation is recited in the claims) which bind a cancer-specific neoepitope (BRAFV600E mutant peptides held to read upon the limitation of a cancer neoepitope, which is cancer-specific (tied to melanoma and not tied to any other diseases) absent a closed definition to further clarify or preclude this interpretation and given its consistency with the instant disclosure (see for example, paragraphs 0026 and 0029 of the instant specification)) where the antibody may be humanized or chimeric (see for example, the abstract, paragraphs 0090-0094 and 0120 of Wistar).
Wistar further teaches the process of using BRAF peptides, such as the mutated BRAF 29-mer having the V600E mutation (neoepitopes), for use in screening antibodies from libraries of antibodies to isolate antibodies that bind the neoepitope(s) (see for example, paragraphs 0004-0006, 0091-0092, and 0124-0125). Wistar further teaches that conventional drug screening techniques may be employed using the peptides described herein. As one example, a method for identifying compounds which specifically bind to a peptide include the steps of contacting a selected peptide with a test compound to permit binding of the test compound to the peptide; and determining the amount of test compound, if any, which is bound to the peptide. Such a method may involve the incubation of the test compound and the peptide immobilized on a solid support (see for example, paragraph 0126).
Reference D, Wistar, and Hacohen et al do not teach that the CDRs are selected from a high-diversity library.
However, Huang et al teach that phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens. The size and quality of libraries are crucial for the success of phage display. Currently, methods for the production of peptide libraries can lead to library sizes from 109 to 1011, with the average library generally containing 107 members. Optimized and novel strategies to generate large antibody libraries have been carried out, increasing the diversity to 1012, noting that M13 phage library display technology is well-known in the art (see for example, pages 4569-4751). Huang et al teach that advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens (see for example, page 4569 at the abstract and pages 4571-4573).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D, Wistar, Hacohen et al, and Huang et al. The artisan would have been motivated to make and use the invention as claimed because Wistar teaches means for raising synthetic, therapeutic antibodies against a cancer-specific neoepitope (see for example, the abstract, paragraphs 0090-0094 and 0120 of Wistar), using a library and screening such that the neoepitope is immobilized on a support. Where Wistar teaches the use of humanized antibodies, the artisan would have found it obvious to take CDRs from the screened library and graft them into a human antibody framework (a scaffold as is consistent with page 17 of the instant specification). Upon further screening to confirm continued specificity, the synthetic antibody having grafted CDRs from the high-diversity library of Wistar as modified by Huang et al in a human scaffold would have been bound to the neoepitope of Wistar as modified by Hacohen et al, said neoepitope being immobilized on a solid support (prior to isolation of the neoepitope-binding antibody). Using the process of Wistar for antibody generation, the artisan would have understood the desirability of selecting a neoepitope that is that is personalized (patient-specific), cancer-specific, and HLA-matched through the means taught by Hacohen et al (see for example, the abstract, figure 1, and the caption of figure 1). Hacohen further teaches that despite years of preclinical efforts and hundreds of clinical studies, therapeutic cancer vaccines have been elusive, but with advances in genome sequencing, it is now possible to identify a new class of tumor-specific antigens derived from mutated proteins that are present only in the tumor which should provide highly specific targets for antitumor immunity (see for example, the abstract of Hacohen et al). The artisan would have further found it obvious, to modify the library used in Wistar to be a high-diversity library in order to allow for better generation and screening of antibodies as taught by Huang et al (noting that even the average phage library generated by traditional means comprises 107 member, which satisfies the definition of a high diversity library suggested by the instant specification (see the claim interpretation section above). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 2, reference D specifies that the neoepitope consists of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, each of which are 9 amino acids in length (see claim 1 of reference D).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D, Wistar, Huang et al, and Hacohen et al. The artisan would have been motivated to make and use the invention as claimed because reference D claims a 9-mer neoepitope suggesting predictable success using a 9-mer neoepitope (see claim 1 of reference D). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 3, reference D does not claim that the neoepitope has a mutation relative to normal tissue.
However, Hacohen et al discuss selection of a neoepitope (a mutated epitope) present in cancer/tumor tissue and not in normal tissue, as discussed in the rejections under 35 USC 103, above (see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D, Huang et al, Wistar, and Hacohen et al. The artisan would have been motivated to make and use the invention as claimed because reference D teaches the antibody (see claims 1 and 11 of reference D) and Hacohen et al teach in their method for selecting a cancer-specific, patient-specific, HLA-matched neoepitope the desirability and predictability of selecting a neoepitope mutated/present in the cancer/tumor tissue relative to (not present in) normal tissue, as discussed in the rejections under 35 USC 103, above (see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al). Where the library ranges in size from 107-109, the result is deemed to be predictable with the library size being an obvious matter of choice. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 8-12, reference D claims an antibody binding a neoepitope (see claim 1 of reference D) wherein the antibody comprises a therapeutic agent which may be a radiologic agent, cytotoxic T cell, or an NK cell (see 1-3 of reference D).
Claims 4 and 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of copending Application No. 19/057,588 (reference D) in view of Wistar, Huang et al, Hacohen et al, Nagorsen et al, and Tembhare et al as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 1-3 for double patenting with respect to reference D in view of Wistar, Huang et al, and Hacohen et al, above, are incorporated herein.
Regarding claim 4, reference D does not teach that the neoepitope is characterized by having a mutation type, strength of expression, and by a predetermined binding affinity towards the HLA-type of the patient. However, Wistar, Huang et al, Hacohen et al, and Tembhare et al make obvious such means of characterization of the neoepitope (as discussed in the rejections of the claims under 35 USC §103; see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al). Moreover, any neoepitope is characterized by the traits because it has some value related to them just by existing as a composition where no further detail is provided to preclude such interpretation. Nagorsen et al teach that HLA-typing is particularly important because it is a prerequisite for successful specific immunotherapy. The HLA-specificity of antigen-derived peptide-epitopes is the basis for specific immunotherapy not only for cancer but also for viral infections (i.e., adoptive transfer of virus-specific T cells). HLA binding of antigen-derived epitopes is where immunotherapy begins. It has been shown that HLA affinity of a peptide can be more important for its immunogenicity than other mechanisms of the antigen-processing machinery (see for example, column 1 of page 1904).
Regarding claim 6, Wistar, Hacohen et al, and Tembhare et al further make obvious matching the HLA-matched neoepitope for MHC-I presentation, as discussed above in the rejections of the claims under 35 USC §103 (see for example. the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al).
Regarding claim 7, Wistar, Hacohen et al, and Tembhare et al further make obvious at least the use of an IgG antibody format or a Fab fragment, as discussed above in the rejections of the claims under 35 USC §103 (see for example, the abstract, paragraphs 0004-0005, 0090-0094, 0120, 153, and table 3 of Wistar; see also for example, the abstract, paragraph 3 of the A case for neoantigens section, figure 1, and the caption of figure 1 of Hacohen et al; see additionally for example, paragraph 2 of the Introduction of Tembhare et al).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D The artisan would have been motivated to make and use the invention as claimed because reference D claims an antibody defined by the same limitations, connected to a therapeutic agent within the scope of the instant claims (of the same scope) (see claims 1-3 and 11 of reference D). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 13 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of copending Application No. 19/057,588 (reference D) in view of Wistar, Huang et al, Hacohen et al, and Shi et al, as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 1-3 and 8-12 for double patenting with respect to Reference D in view of Wistar, Hacohen et al, and Huang et al above, are incorporated herein.
Regarding claim 13, reference D, Wistar, Huang et al, and Hacohen et al, do not teach that T cell has a chimeric receptor, an scFv (format of the antibody against the neoepitope), and a CD16.
However, Shi et al teach that to expand the applications for T cell-based immunotherapy in cancer, researchers have constructed similar “universal” CARs (uCAR) that utilize anti-fluorescein isothiocyanate (FITC) scFv (see for example, Figure 1C and its caption). These uCAR T cells recognize various cancer types when bound to FITC-labeled or biotinylated antigen-specific mAbs or scFvs, resulting in efficient target lysis, T-cell proliferation, and cytokine production, effectively treating the tumor. Shi et al teach that more recently, Kudo et al constructed a novel uCAR containing the high-affinity CD16 (FCGR3A) V158 variant (a genetically modified CD16). CD16V-based uCAR T cells have bound humanized antibodies with higher affinity and engagement of the CD16V-uCAR provoked T cell activation, exocytosis of the lytic granules and sustained proliferation, thereby enhancing the therapeutic effects of the T cell-based anti-tumor therapy. Further, the co-administration of CD16V uCAR T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo (see for example, the CAR binding domain section).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference D, Wistar, Huang et al, Hacohen et al, and Shi et al. The artisan would have been motivated to make and use the invention as claimed because Shi et al teach that a uCAR T-cell having a genetically modified CD16V may be paired with an scFv (in the ectodomain) which aids in targeting the uCAR T-cell to the tumor tissue where the modified CD16 then enhances the antitumor effects (for example, lysis) of the T-cell for tumor treatment (see for example, the Figure 1 and its caption and CAR binding domain section). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of copending Application No. 19/057,588 (reference D) in view of Wistar, Huang et al, Hacohen et al, and Carter, as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 1-3 and 8-12 for double patenting with respect to reference D in view of Wistar, Huang et al, and Hacohen et al above, are incorporated herein.
Regarding claim 14, reference D, Wistar, Huang et al, and Hacohen et al, do not teach that NK cell has a high-affinity CD16 FcγR bound to the Fc region of an IgG, synthetic antibody binding a cancer neoepitope.
However, Carter teaches antibodies have been a common anti-cancer treatment, but that their efficacy has been limited because they are underpowered (see for example, paragraph 1 of the abstract at page 3/51, the paragraph bridging pages 3/51-4/51, and the second paragraph of page 4/51). Carter then teaches that antibodies may be paired with stronger anti-cancer therapeutics which addresses the low cytotoxicity of the antibody and enhances the cytotoxic moiety by targeting it to the tumor (see for example, the final key point bullet point on page 2/51, the paragraph bridging pages 4/51-5/51, Figures 1 and 2 and their respective captions and pages 5/51-6/51 and 9/51-10/51, the enhancing effector function section at pages 8/51-11/51, and the bispecific antibodies section at pages 18/51-19/51). Carter teaches that human antibodies, particularly IgG1 and IgG3, can potentially direct the killing of tumour cells by antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) (see for example, Figure 2 and its caption). Carter teaches natural killer (NK) cells have cytotoxic activity against tumor cells and that, when paired with a bispecific antibody, the NK cell may be targeted to tumor cells it would otherwise ignore (see for example, Figure 1 and the caption of figure 1b and pages 5/51-6/51, the enhancing effector functions section at pages 8/51-11/51, the bispecific antibodies section at pages 18/51-19/51, and Figure 2 and its caption at pages 9/51-10/51). Carter additionally teaches that ADCC is triggered by an interaction between the Fc region of an antibody that has bound, through its antigen-binding region, to a tumour cell and the Fcγ receptors (FcγRs), particularly FcγRI and FcγRIII, on immune effector cells such as neutrophils, macrophages and natural killer cells (see for example, paragraph 1 of the enhancing effector functions section at pages 8/51-9/51 and figure 2 and its caption at page 9/51). The tumour cell is eliminated by phagocytosis or lysis, depending on the type of mediating effector cell, thus treating the tumor (see for example, Figure 2 and its caption). Carter additionally teaches that bispecific antibodies that bind to a tumour-associated antigen and a so-called trigger antigen on an immune effector cell can recruit the effector cell to kill a tumour cell that it would otherwise disregard. The most extensively used trigger molecules are FcγRIII (CD16) on natural killer cells (see for example, paragraph 2 of the Bispecific Antibodies section on page 9/51-10/51). Carter further teach that studies indicate the potential for increasing the antitumour activity of an antibody by manipulating the Fc region to increase its affinity for the activation receptor(s) and/or by abrogating its ability to bind to the inhibitory receptor.
While Carter does not explicitly teach that the NK cell is linked to an antibody against a neoantigen, Carter teaches that Fc-FcγR interactions are important for therapeutic cytotoxicity (ADCC) (see for example, paragraphs 2-3 of the Enhancing Effector Functions section on page 10/51 bridging 11/51 and Figure 2 and its caption). Carter further teaches that NK cells most commonly have a high-affinity CD16 FcγR which may bind to the Fc region of an IgG antibody. Carter appears to show this conformation (an effector cell bearing an FcγR bound to the Fc region of an antibody) wherein the antibody targets the effector cell to the tumor, thereby effecting therapeutic lysis (see for example, paragraphs 2-3 of the Enhancing Effector Functions section on page 10/51 bridging 11/51 and Figure 2 and its caption).
The MPEP provides that:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In reKerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In reCrockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parteQuadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious),”
(see MPEP section 2144.06(I)).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Huang et al, Hacohen et al, Tembhare et al, and Carter. Here, it would have been obvious to a one of ordinary skill in the art to combine an antibody for targeting cancer, such as the therapeutic, synthetic, IgG antibody of Wistar with a therapeutic effector cell, such as the NK cell bearing a high affinity CD16 of Carter. The artisan would have been motivated to make and use the invention as claimed because Carter teaches that these components can be used individually to treat cancer and that they can be used, at least, in tandem to treat cancer (see for example, paragraph 1 of the abstract at page 3/51, the paragraph bridging pages 3/51-4/51, the second paragraph of page 4/51, the enhancing effector functions section at pages 8/51-11/51, the bispecific antibodies section at pages 18/51-19/51, and Figure 2 and its caption at pages 9/51-10/51). One of ordinary skill in the art would have found it obvious to attach the antibody to the NK cell as taught by Carter (see fig 2 and its caption). One of ordinary skill in the art would have been motivated to use the resulting composition to treat cancer because Carter teaches this is a targeted and effective treatment for effecting tumor lysis or phagocytosis (treatment) (see for example, figure 2 and its caption at pages 9/51-10/51) The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 12-15, and 17-19 of copending Application No. 19/057,588 (reference D) in view of Wistar, Huang et al, Hacohen et al, Nagorsen et al, Tembhare et al, and Qi et al, as applied to the claims in the rejections under 35 USC 103, above. The claims concern compositions/constructs targeting cancer neoepitopes which appear to comprise overlapping structures capable of performing identical functions.
Note that the teachings and arguments referenced and discussed in the rejections of claims 4 and 6-12 for double patenting with respect to Reference D in view of Wistar, Huang et al, Hacohen et al, and Tembhare et al above, are incorporated herein.
Reference D, Hacohen et al, Wistar, Huang et al, Nagorsen et al, and Tembhare et al, do not teach that the neoepitope that the antibody binds is filtered for a subcellular location.
However, Qi et al teach a web interface Spatial Epitope Prediction server for Protein Antigens (SEPPA 2.0) which is a conformational epitope prediction algorithm. Qi et al teach that this algorithm has been improved by taking into account the subcellular location of the protein antigen (such as a neoepitope) (see for example, the abstract of Qi et al). As noted above, the steps of filtering an epitope by measuring and selecting based upon n-mer size/length, strength of expression, HLA-matching, and, in view of Qi et al, subcellular location, were known in the art and represent a finite number of steps which may be combined in a finite number of sequences. The prior art combination cited teaches that the filters are helpful in selecting an epitope/neoepitope against which a synthetic antibody may be raised for cancer treatment/therapy, where adding in a filter for subcellular location further aids/enhances protein antigen (neoepitope) selection. While the claims do not specifically require any given order of filtering (such as n-mer, then strength, the HLA, and then subcellular location), any order of the filtering steps would have been obvious in light of the prior art for the artisan to try, noting that the elected invention is a composition, making the antibody, either a product or a product-by-process, in which case the process of making (including the process of neoepitope selection) is irrelevant to the question of novelty/nonobviousness where the prior art product makes obvious the product instantly claimed, absent a convincing and evidenced showing of an unexpected improvement resulting from the process by which the product is made. Here, no such improvement has been demonstrated.
While the claims do not specifically require any given order of filtering (such as n-mer, then strength, the HLA, and then subcellular location), any order of the filtering steps would have been obvious in light of the prior art for the artisan to try, noting that the elected invention is a composition, making the antibody, either a product or a product-by-process, in which case the process of making (including the process of neoepitope selection) is irrelevant to the question of novelty/nonobviousness where the prior art product makes obvious the product instantly claimed, absent a convincing and evidenced showing of an unexpected improvement resulting from the process by which the product is made. Here, no such improvement has been demonstrated.
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference C, Wistar, Huang et al, Hacohen et al, Tembhare et al, and Qi et al. The artisan would have been motivated to make and use the invention as claimed because Qi et al teach that computational identification of immunogenic regions/segments in a given protein antigen has provided increasing assistance in guiding the experimental validation (wherein their improved model which includes subcellular location filtering increased area under the curve (AUC) and decreased the number of false positives)(see for example, the abstract and the first 2 paragraphs of the Introduction of Qi et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
New-Double Patenting
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.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11421016 B2 (reference B) as applied to claims 1-5 and 7-10 above, in view of Wistar and Hacohen et al as cited in the rejections under 35 USC §103 above. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims teach the process resulting in a product encompassed within the instant claims.
Regarding claim 6, Wistar further teaches the use of a MHC class I (HLA) binding prediction score (held to read upon the limitation of HLA MHC class I matched epitope in light of paragraph 0034 of the instant specification used to provide insight into what is meant by said recitation) to filter/select for cancer neoepitopes (BRAFV600E) (see for example, paragraphs 0008, 0040, 0153 and Table 3 of Wistar).
Moreover, Hacohen et al teach patient-specific (personalized) cancer-specific (tumor-specific) neoepitopes (mutated peptides) are identified on the basis of predictive HLA-binding algorithms (see for example, the caption of figure 1).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference B, Wistar, and Hacohen et al. The artisan would have been motivated to make and use the invention as claimed because the combined references suggest such neoepitope has a better chance of targeting the tumor and to decreasing immune evasion by selecting a neoepitope less likely to be downregulated (as taught by Hacohen et al (see for example, paragraph 3 of the A case for neoantigens section). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 8, 11-12, and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11421016 B2 (reference B) as applied to claims 1-5 and 7-10 above, in view of Wistar, Hacohen et al, and Carter et al as cited in the rejections under 35 USC §103 above. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims teach the process resulting in a product encompassed within the instant claims.
Regarding claim 8, the combined references do not explicitly teach the composition of instant claim 1 wherein a therapeutic agent is coupled to the synthetic antibody.
However, Carter teaches that a variety of non-cellular therapeutic agents may be linked to an antibody for targeting the therapeutic agent to the cancer (see for example, the Key points bullet points at pages 1/51-2/51 and figure 1 and its caption).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Carter teaches that various anti-cancer moieties, such as a radionuclide or prodrug, may be linked to an antibody for pre-targeting to reduce systemic toxicities associated with radioimmunotherapy and cytotoxic chemotherapy, respectively (see for example, pages 19/51 21/51). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claims 11-12 and 14, reference B does not explicitly teach an effector cell as the additional therapeutic and/or the antibody bound to the genetically-mutated, high-affinity FcγRIII (CD16) of an NK cell.
However, Carter teaches that antibodies have been a common anti-cancer treatment, but that their efficacy has been limited because they are underpowered (see for example, paragraph 1 of the abstract at page 3/51, the paragraph bridging pages 3/51-4/51, and the second paragraph of page 4/51). Carter then teaches that antibodies may be paired with stronger anti-cancer therapeutics which addresses the low cytotoxicity of the antibody and enhances the cytotoxic moiety by targeting it to the tumor (see for example, the final key point bullet point on page 2/51, the paragraph bridging pages 4/51-5/51, Figures 1 and 2 and their respective captions and pages 5/51-6/51 and 9/51-10/51, the enhancing effector function section at pages 8/51-11/51, and the bispecific antibodies section at pages 18/51-19/51). Carter teaches that human antibodies, particularly IgG1 and IgG3, can potentially direct the killing of tumour cells by antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) (see for example, Figure 2 and its caption). Carter teaches natural killer (NK) cells have cytotoxic activity against tumor cells and that, when paired with a bispecific antibody, the NK cell may be targeted to tumor cells it would otherwise ignore (see for example, Figure 1 and the caption of figure 1b and pages 5/51-6/51, the enhancing effector functions section at pages 8/51-11/51, the bispecific antibodies section at pages 18/51-19/51, and Figure 2 and its caption at pages 9/51-10/51). Carter additionally teaches that ADCC is triggered by an interaction between the Fc region of an antibody that has bound, through its antigen-binding region, to a tumour cell and the Fcγ receptors (FcγRs), particularly FcγRI and FcγRIII, on immune effector cells such as neutrophils, macrophages and natural killer cells (see for example, paragraph 1 of the enhancing effector functions section at pages 8/51-9/51 and figure 2 and its caption at page 9/51). The tumour cell is eliminated by phagocytosis or lysis, depending on the type of mediating effector cell, thus treating the tumor (see for example, Figure 2 and its caption). Carter additionally teaches that bispecific antibodies that bind to a tumour-associated antigen and a so-called trigger antigen on an immune effector cell can recruit the effector cell to kill a tumour cell that it would otherwise disregard. The most extensively used trigger molecules are FcγRIII (CD16) on natural killer cells (see for example, paragraph 2 of the Bispecific Antibodies section on page 9/51-10/51). Carter further teaches that studies indicate the potential for increasing the antitumour activity of an antibody by manipulating the Fc region to increase its affinity for the activation receptor(s) and/or by abrogating its ability to bind to the inhibitory receptor.
While Carter does not explicitly teach that the NK cell is linked to an antibody against a neoantigen prior to any therapeutic use, Carter teaches that Fc-FcγR interactions are important for therapeutic cytotoxicity (ADCC) (see for example, paragraphs 2-3 of the Enhancing Effector Functions section on page 10/51 bridging 11/51 and Figure 2 and its caption). Carter further teaches that NK cells most commonly have a high-affinity CD16 FcγR which may bind to the Fc region of an IgG antibody. Carter appears to show this conformation (an effector cell bearing an FcγR bound to the Fc region of an antibody) wherein the antibody targets the effector cell to the tumor, therefore effecting therapeutic lysis (see for example, paragraphs 2-3 of the Enhancing Effector Functions section on page 10/51 bridging 11/51 and Figure 2 and its caption).
The MPEP provides that:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In reKerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In reCrockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parteQuadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious),”
(see MPEP section 2144.06(I)).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. Here, it would have been obvious to a one of ordinary skill in the art to combine an antibody for targeting cancer, such as the therapeutic, synthetic, IgG antibody of Wistar with a therapeutic effector cell, such as the NK cell bearing a high affinity CD16 of Carter. The artisan would have been motivated to make and use the invention as claimed because Carter teaches that these components can be used individually to treat cancer and that they can be used, at least, in tandem to treat cancer (see for example, paragraph 1 of the abstract at page 3/51, the paragraph bridging pages 3/51-4/51, the second paragraph of page 4/51, the enhancing effector functions section at pages 8/51-11/51, the bispecific antibodies section at pages 18/51-19/51, and Figure 2 and its caption at pages 9/51-10/51). One of ordinary skill in the art would have found it obvious to attach the antibody of Wistar to the NK cell as taught by Carter (attaching the Fc of the antibody to the CD16 (FcγR) of the NK cell as shown and described by the cited teachings of Carter)(see for example, fig 2 and its caption). One of ordinary skill in the art would have been motivated to use the resulting composition to treat cancer because Carter teaches this is a targeted and effective treatment for effecting tumor lysis or phagocytosis (treatment)(see for example, figure 2 and its caption at pages 9/51-10/51). There are 2, finite options for attachment of the IgG Fc to the CD16 of the NK cell, before or after administration. The artisan, looking to meet the long felt need of treating cancer would have wanted to take advantage of the enhanced ADCC and targeting taught by Carter and would have found it obvious to try to connect the Fc of the IgG antibody, such as that of Wistar, to the high-affinity CD16 commonly possessed by an NK cell allowing for attachment to said Fc region (see MPEP §2143(I)(E)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claims 8 and 11-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11421016 B2 (reference B) as applied to claims 1-5 and 7-10 above, in view of Wistar, Hacohen et al, and Shi et al as cited in the rejections under 35 USC §103 above. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims teach the process resulting in a product encompassed within the instant claims.
Regarding claims 8 and 11-13, Wistar teaches an IgG antibody against a cancer neoepitope, as discussed above.
Reference B in view of Wistar does not explicitly teach an effector cell as the additional therapeutic and/or that the T-cell has an scFv ectodomain with a genetically modified CD16 receptor.
However, Shi et al teach that to expand the applications for T cell-based immunotherapy in cancer, researchers have constructed similar “universal” CARs (uCAR) that utilize anti-fluorescein isothiocyanate (FITC) scFv (see for example, Figure 1C and its caption). These uCAR T cells recognize various cancer types when bound to FITC-labeled or biotinylated antigen-specific mAbs or scFvs, resulting in efficient target lysis, T-cell proliferation, and cytokine production, effectively treating the tumor. Shi et al teach that more recently, Kudo et al constructed a novel uCAR containing the high-affinity CD16 (FCGR3A) V158 variant (a genetically modified CD16). CD16V-based uCAR T cells have bound humanized antibodies with higher affinity and engagement of the CD16V-uCAR provoked T cell activation, exocytosis of the lytic granules and sustained proliferation, thereby enhancing the therapeutic effects of the T cell-based anti-tumor therapy. Further, the co-administration of CD16V uCAR T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo (see for example, the CAR binding domain section).
It would have been prima facie before the effective filing date of the invention obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Wistar, Hacohen et al, reference B, and Shi et al. The artisan would have been motivated to make and use the invention as claimed because Shi et al teach that a uCAR T-cell having a genetically modified CD16V may be paired with an scFv (in the ectodomain) which aids in targeting the uCAR T-cell to the tumor tissue where the modified CD16 then enhances the antitumor effects (for example, lysis) of the T-cell for tumor treatment (see for example, Figure 1 and its caption and CAR binding domain section of Shi et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Reponses:
A. Applicant requests withdrawal of the rejections for lack of written description. Applicant points to paragraph 0012 of the specification as describing the CDRs. Applicant alleges that merely functional limitations are descriptive because antibodies not meeting the functional limitations would be outside of the scope of the claims. Applicant alleges the claimed genus requires, and is described adequately by, ‘a scaffold portion and a CDR graft portion selected from a high-diversity library’ where the antibody is bound to a synthetic, immobilized peptide that has a sequence of a patient- and cancer-specific HLA-matched cancer neoepitope, and the synthetic antibody specifically binds said epitope. Applicant notes that the written description does not require identification of specific structure associated with claimed function. Applicant alleges that citation of Amgen Inc. v Sanofi is improper because the case only pertains to the enablement requirement and is irrelevant to the written description requirement (see pages 5-11 of the 02/20/2026 remarks).
Response: Paragraph 0012 only mentions that the antibody has CDRs. This is common knowledge in the art and is not sufficient to describe the claimed genus of antibodies, but merely shows the breadth of what Applicant claims, but has failed to show possession of. Applicant points out that no particular structure is required to be associated with the claimed function (a structure-function correlation). This is true. Written description may be met by such a structure-function correlation or by disclosure of a representative number of species. The instant disclosure fails to meet the written description requirement by either route as no species are disclosed and, as Applicant notes, no structure-function correlation has been disclosed. The generic disclosure that the antibody has a scaffold portion and a CDR graft portion selected from a high-diversity library does not disclose any structure which describes the genus such that the artisan may envisage the members of the claimed genus. The argument that the antibodies are described by epitope and function alone, because non-binding antibodies are beyond the scope of the claim entirely fails to be responsive to the requirements of 35 USC 112(a) and is unpersuasive to overcome the rejections for failure to provide written description. Regarding Applicant’s assertions of Amgen Inc. v Sanofi (872 F.3d 1367 (Fed. Cir. 2017)), Applicant is encouraged to review pages 1376-1378 where the opinion discusses the written description requirement at length. The flowing quotation is generally reflective:
“We cannot say that this particular con text, involving a ‘‘newly characterized anti gen’’ and a functional genus claim to corresponding antibodies, is one in which the underlying science establishes that a finding of ‘make and use’ (routine or conventional production) actually does equate to the required description of the claimed products. For us to draw such a conclusion, and transform a factual issue into a legally required inference, we would have to declare a contested scientific proposition to be so settled as to be entitled to judicial notice. That we cannot do,”
See for example, Amgen Inc. v Sanofi (872 F.3d 1367 (Fed. Cir. 2017)) at column 1 of page 1378. Further, the rejection is supported by more than the citation to the Amgen v. Sanofi case, which may be observed by reviewing the rejection as reproduced above. Therefore, the rejections of the claims 1-14 for lack of written description are maintained at this time.
B. Applicant argues for withdrawal of the rejections under 35 USC §103, alleging that Wistar only teaches antibodies that bind BRAFV600E and the instant claims are directed towards selecting an antibody that binds the patient-cancer-specific HLA-matched cancer neoepitopes, the claimed approach being more robust. Applicant discusses that Wistar uses particular means to arrive at the composition (see for example, page 13 of the 02/20/2026 remarks) which differ from the means used by Applicant.
Response: Wistar only needs to teach antibodies to a single neoepitope to meet the claims as drafted. Moreover, Applicant’s characterization of the claims and argument(s) to distinguish them over the cited prior art is unpersuasive because the claims are to a composition, not a method of antibody selection or antibody generation. The means Wistar use to arrive at the composition versus the means used by Applicant in the disclosure are not pertinent to the instant claims because the claims being examined are process claims. Applicant is advised that product claims and product-by-process claims may be anticipated or made obvious by art teaching/making obvious the product irrespective of the method by which the product is produced.
C. Applicant argues that Wistar and Hacohen et al teach divergent/contradictory matter and would not be combined leading to the claimed matter because Wistar teaches away from a personalized or patient-specific neoepitope approach, such that there is no motivation to combine Wistar, Hacohen et al, and Huang et al (see for example, pages 13-14 of the 02/20/2026 remarks).
Response: This is unpersuasive. Wistar teaches means for neoepitope selection where Hacohen et al teach further filtering/inclusion criteria (HLA-matching and the use of a patient-specific neoepitope). These teachings are not contradictory as one is led by Wistar to raise one more synthetic antibodies by means known in the art to a neoepitope where Hacohen et al guide in further filtering steps in selecting the neoepitope to raise and antibody against and screen for as taught by Wistar in view of Huang et al. There is no stated reason for why this modification would not have been obvious and compatible with the method of antibody generation and screening taught by Wistar. Further, as there is no definition of a personalized or patient-specific neoepitope, so long as the patient has the neoepitope, it is patient-specific as claimed. There is nothing in the disclosure that requires that the patient-specific neoepitope is uncommon. Furthermore, a true “teaching away" from a concept must be explicit, not just an otherwise general suggestion. Additionally, “the prior art' s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In this case, Wistar teaches a composition comprising an antibody generated from a library, the antibody specifically binding to a neoepitope which is patient and cancer specific, where the respective terms are interpreted with their broadest reasonable interpretation (a neoepitope that a patient has that is exhibited by said patient’s cancer) in the absence of a more narrow/alternative/preclusive definition in the instant disclosure. The claims do not require, nor does the specification describe or support, that the neoepitope is uncommon/rare. Thus, Wistar is not deemed to teach away from what is claimed and arguments regarding the prevalence of the neoepitope rely on new matter which is unclaimed. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Therefore, the rejections of record are maintained. Applicant relies upon this argument in their request for withdrawal of the rejections under 35 USC §103 of further claims, the argument likewise being unpersuasive such that the rejections are maintained.
D. Applicant analyzes the Hacohen reference in isolation regarding the recited n-mer size (see instant claim 2) and the filter process (specifically subcellular filtering; see for example, instant claim 5) (see for example, pages 14-15 of the 02/20/2026 remarks).
Response: Hacohen is never cited in isolation, but is part of one or more non-obvious rejections relying upon a combination of references. For example, instant claim 2, reciting the n-mer size of 5-30 amino acids, is rejected over the combination of Wistar, Hacohen et al, and Huang et al. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant fails to account for and argue or rebut the substance of the pending rejections. Therefore, the rejections are maintained.
E. Applicant argues for withdrawal of the rejections under 35 USC §103, alleging that Tembhare teaches quantification of antigen levels but does not teach a method for filtering for strength of expression (see for example, pages 16-17 of the remarks dated 02/20/2026)..
Response: The broadest reasonable interpretation of filtering by strength of expression encompasses determining expression level/strength and selecting for a neoepitope having a higher expression level/strength to increase efficacy/likelihood of tumor targeting with decreased likelihood of immune evasion as taught by Tembhare. There is no other interpretation described or supported by the disclosure, but there is no iteration of why the teachings of Tembhare do not make obvious the instant limitation of filtering by strength of expression. There being no argument top consider, the rejections are maintained.
F. Applicant argues for withdrawal of the rejections under 35 USC §103, because Chari et al allegedly do not teach indirect coupling and do not teach coupling (making an ADC) of an antibody against a patient-specific, cancer-specific neoepitope (see pages 17-18).
Response: The claims do not require indirect coupling. Therefore, even if Chari et al did not teach indirect coupling, Chari et al would still be applicable art teaching coupling of a synthetic antibody to a therapeutic agent. However, in the interest of advancing prosecution, the Examiner notes that the instant specification inly mentions indirect coupling once, stating that “ indirect coupling [is coupling] in which at least one additional element is located between the two elements,” (see for example, page 18 of the instant specification). Chari et al teach coupling of a generic antibody (such as the synthetic antibody meeting the limitations of instant claim 1 (the prior art antibody) to a maytansinoid (a well-known cytotoxic payload used in ADCs via a heterobifunctional linker (see for example, section 5.1.3 at page 3805 of Chari et al) which would read on a hypothetical recitation of indirect coupling. Further, there is nothing in Chari et al to suggest that the antibody resulting from the prior art would not function to produce a functional ADC (coupling of a cytotoxic payload to the antibody). Moreover, regarding Applicant’s assertion that Chari et al do not teach the use of radio isotopes, PET detectable isotopes, SPECT detectable isotopes, or affinity agents, it is noted that the art need not teach these limitations in order to meet claim 10 because instant claim 10 recited a chemotherapeutic drug, a radio isotope, PET detectable isotopes, SPECT detectable isotopes, or affinity agents are alternative options connected by the word ‘or’ such that only one must be taught. As discussed in the rejection above and implicitly acknowledged in Applicant’s response. Chari et al teach the use of a chemotherapeutic drug. Therefore, the rejections of record are maintained.
G. Applicant argues for withdrawal of the obviousness rejections over Carter alleging that Carter does not teach that the NK cell optional has a CD16 or that the Fc of the antibody is attached to the CD16 of the NK cell (see for example, page 20 of the 02/20/2026 remarks).
Repose: Applicant is encouraged to review the rejection of record and the cited teachings. Carter does tach that NK cells have a high-affinity CD16 which may bind to the Fc region of an IgG. Carter teaches several advantages of such attachment for treating cancer. This argument is unpersuasive and the rejections are maintained.
H. Applicant argues for withdrawal of the obviousness rejections over Shi et al alleging that Shi et al does not teach that the NK cell optional has a CD16 or that the Fc of the antibody is attached to the CD16 of the NK cell (see for example, pages 20-21 of the 02/20/2026 remarks).
Response: The teachings of Shi et al are only disclosed in isolation and are never connected to the teaching of the combined references. It is noted that Shi et al is never relied upon on its own, but is included in a nonobviousness rejection where the combined teachings of all of the cited references are required to meet the claim. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant fails to account for and argue or rebut the substance of the pending rejections. Therefore, the rejections are maintained.
I. Applicant did not substantively address the rejections of the claims for double patenting (see pages 21-24 of the 02/20/2026 remarks).
Response: Applicant disagrees with the rejection and requests that the rejection be held in abeyance until there is allowable subject matter in the application. This has been fully considered but is not found to be persuasive. Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states: “A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.” “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03.Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner.” See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis added). Accordingly, the rejection is maintained and is expressly not held in abeyance.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO2014052707A2 (as cited on the 03/13/2025 IDS) is deemed relevant to the process of arriving at the neoantigen through sampling and filtering for a patient- and cancer-specific neoepitope that comprises a mutation and is HLA-matched.
Fritsch et al (“HLA-Binding Properties Of Tumor Neoepitopes In Humans," Cancer Immunology Research, Vol. 2, No. 6, June 2014; as cited on the 03/13/2025 IDS) teach that cancer genome sequencing has enabled the rapid identification of the complete repertoire of coding sequence mutations within a patient's tumor and facilitated their use as personalized immunogens (finding cancer-specific, patient-specific neoepitopes for targeted immunotherapy). Although a variety of techniques are available to assist in the selection of mutation-defined epitopes, the ability of the peptide to bind to patient MHC is a key gateway to peptide presentation. Advanced algorithms using neural network-based learning approaches have been developed to capitalize on large amounts of data describing peptides that bind with different strengths to a wide variety of class I MHC molecules. These algorithms allow rapid in silico prediction of peptide-binding strength to patient-specific MHC alleles, and potentially enable a more rapid and less restrictive approach to filter the list of candidate neoepitopes (neoantigens) from sequencing data (see for example, the abstract and the In silico prediction of peptide-MHC binding section of Fritsch et al).
Ylera et al (Anal Biochem. 2013 Oct 15;441(2):208-13. doi: 10.1016/j.ab.2013.07.025. Epub 2013 Jul 29) discusses the use of phage display libraries and screening for antibody development.
US 8652473 B2 (citation 3 under US Patents on the 09/02/2025 IDS) and US20110293637 A1 are deemed relevant.
The cited references under US Patent Application Publications heading on the 09/02/2025 IDS are deemed relevant.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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