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 amendment
Applicants’ amendment filed 10/6/2025 has been received and entered. Claims 1-2, 8-9 and 17 have been amended, and claims 6-7, 12 have been cancelled.
Claims 1-5, 8-11, 13-20 filed 4/21/2021 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-12 and the peptide set forth in SEQ ID No 8 in the reply filed on 2/20/2025 was acknowledged.
No new arguments are provided in the instant response. The claim amendments appear consistent with the previously examined claims.
Claims 1-5, 8-11, 13-20 filed 4/21/2021 are pending. Claims 13-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/20/2025.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The examiner has required restriction between product or apparatus claims and process claims. In this case Applicants have elected the method, not the product.
Claims 1-5, 8-11, drawn to a method of determining an antigen by comparing normal and altered cells are currently under examination.
Priority
This application filed 4/21/2021 is a 371 National stage filing of PCT/US19/58582 filed 10/29/2019 which claims benefit to US provisional application 62/752149 filed 10/29/2018.
Applicant does not comment in the instant response on the summary of priority.
Information Disclosure Statement
It was noted that the listing of references in the specification is not a proper information disclosure statement, citing for example page 7 line 34.
No new IDS, nor any comments about the citation is provided in this response.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 12 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for referring to Table 1 is withdrawn.
Claim 12 has been cancelled rendering the rejection moot as indicated by Applicants.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5, 8-11 stand rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claim analysis
Claim 1 has been amended and still is generally directed to identifying differences in the genome of cancer cells that were generated as a consequence of treating cells with an agent that damages the genomic DNA. More specifically, claim 1 has been amended to provide a more detailed step of identifying alterations in DNA by reverse transcribing mRNA in the cells and observing variations/mutations that may have occurred as a consequence of the chemotherapy, and an additional final step for synthesizing that has an alteration has been added. Claim 1 requires identification and when present or identified synthesis of possible variants that are identified. The method requires treating cancer cells with a chemotherapy and given the art and guidance of the specification it should be an agent that damages DNA such that mutations are introduced, then evaluating treated and untreated cancer cell sequences of mRNA from open reading frames and providing for variants that could encode a variant protein after damaging the DNA. Dependent claims set forth the variant sequences represent multiple possible antigenic sites in a protein, the cells are human and comprise a mutated p53 (an oncogene important as a cell cycle checkpoint and in DNA repair when normal), and the possible use of identified sequences as possible targets or antigens that could serve as a vaccine.
Response to Applicants arguments
Applicants note the amendments to the claims, and argue that cDNA is patent eligible because it is not naturally occurring citing Myriad (2013). Applicants argue that the present claims are analogous because they encompass making cDNA from mRNA, which then can be analyzed for alterations.
In response, the steps of converting mRNA into cDNA is acknowledged and has been considered under step 2B as an additional element. Support for ‘cDNA’ can be found twice in the present specification in describing how CD45 cells were analyzed, and does not appear to be the nature of the present invention, nor with the general description a new or novel approach of obtaining DNA from RNA for sequencing purposes. In view of the art as a whole, a step of RT to make cDNA is not new or novel, and was well known to be used to provide libraries of mRNA that is present in a cell. Using a method step to convert mRNA into cDNA is not a point of patentability, and is inconsistent with the fact pattern of Myriad and the logic pertaining to cDNA. First, cDNA is DNA, and it is genomic DNA that provides the basis of the mRNA produced. In the basis of Myriad, the courts reasoned that some of the sequences for the BRCA gene did not contain the introns present in the genomic DNA, and thus while mRNA is natural (a genomic sequence without an intron sequence), the DNA sequence that was made from it was RNA somehow represented a new sequence that was not known. There is no logic in the decision that simply providing cDNA of a mRNA is patent eligible, and Justice Thomas in the Supreme Court appeared to be discussing and considering the information contained in the sequence, not the process itself. For example, if there were no introns, the cDNA would be indistinguishable from any other form of DNA, so simply calling a sequence cDNA is not by itself patent eligible. Given the breadth of the claims and generic recitation and the lack of any particular or new guidance for the process of reverse transcribing RNA into DNA, Applicants arguments are not found persuasive. Therefore, for the reasons above and of record, the rejection is maintained.
The basis of the 101 analysis is provided for completeness of the record.
For step 1 of the 101 analysis, the claims are found to be directed to a statutory category of a method.
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of accessing sequence data for differences between treated and untreated cell sources. The step of determining open reading frames then aligning and comparing sequence to arrive at the identification of differences in sequences are considered instructional steps (steps ii)-iii)). In view of the specification and art of record, the claims require computing similarity scores with the broad steps of receiving data, computing a similarity score and thus determine a variant that is present from the two different sequence sources. The judicial exception is a set of instructions for analysis of sequence data and appears to fall into the category of Mental Processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion). The breadth of “determining” and “comparing” encompasses non-transformative visual assessment of aligned sequences to determine any possible differences. This breadth does not impose a meaningful limit on the claim scope, such that all others are not precluded from using the natural principle of observing genomic DNA differences between two different cells. The steps of the judicial exception are very generally recited, and the combination together reasonably interpreted as mere data gathering and analysis. To the extent the method can be practiced using a computer, computing, constructing datasets and using statistical models was well understood, conventional, and routinely performed in the art at the time the application was filed. Furthermore, the limitation that the identified sequences be used in a vaccine does not change the steps to be performed. See MPEP § 2106.05(g) for a discussion on adding insignificant extra-solution (both pre-solution and post-solution) activity to the judicial exception. See also MPEP § 2106.05(h) for a discussion on generally linking the use of a judicial exception to a particular technological environment or field of use.
Recent guidance from the office requires that the judicial exception be evaluated under a second prong to determine whether the judicial exception is practically applied. In the instant case, the claims suggest that any variation found be used for a vaccine and that a protein be made representing the vaccine antigen and represents an additional element. This judicial exception requires steps recited at high level of generality and combined with the additional element are considered an intended use or for further testing, and is not found to be a practical application of the judicial exception as broadly set forth even though it suggests the product would be a ‘vaccine’. There is no evidence that the difference serve as antigenic sites and importantly would serve to function as a vaccine as suggested in the claims. Although the claims recites “for use in the cancer vaccine’, the courts have also identified limitations that did not integrate a judicial exception into a practical application; for example, merely including instructions to implement or use an abstract idea as discussed in MPEP § 2106.05(f).
For step 2B of the 101 analysis, each of the independent claims recites additional elements and are found to be the steps of taking the sequence data and generating a protein based on the open reading frame. With no evidence that differences serve as antigens or vaccines the claims do not provide for any additional element to consider under step 2B as practical application beyond providing an observation that can be further characterized. To the extent the judicial exception can be practiced using a computer to analyze sequence read data from the two cell sources, it is noted that in explaining the Alice framework, the Court wrote that "[i]n cases involving software innovations, [the step one] inquiry often turns on whether the claims focus on the specific asserted improvement in computer capabilities or, instead, on a process that qualifies as an abstract idea for which computers are invoked merely as a tool." The Court further noted that "[s]ince Alice, we have found software inventions to be patent-eligible where they have made non-abstract improvements to existing technological processes and computer technology." Moreover, these improvements must be specific -- "[a]n improved result, without more stated in the claim, is not enough to confer eligibility to an otherwise abstract idea . . . [t]o be patent-eligible, the claims must recite a specific means or method that solves a problem in an existing technological process."
As indicated in the summary of the judicial exception above and in view of the teachings of the specification, the steps are drawn to analysis of sequence data. While the instruction could be stored on a medium and could be implemented on a computer, together the steps do not appear to result in significantly more than a means to compare sequences. The judicial exception of the method as claimed can be performed by hand and in light of the previous claims to a computer medium and in light of the teaching of the specification on a computer. In review of the instant specification the methods do not appear to require a special type of processor and can be performed on a general purpose computer. Based upon an analysis with respect to the claim as a whole, claims 1-12 do not recite something significantly different than a judicial exception. Claims 1-12 are directed towards a method of receiving sequence data and comparing the data to identify variant sequences between two difference cell sources. Dependent claims set forth additional steps which are more specifically define the considerations and steps of calculating, and comparing, and do not add additional elements which result in significantly more to the claimed method for the analysis.
One way to overcome a rejection for non-patent-eligible subject matter is to persuasively argue that the claimed subject matter is not directed to a judicial exception. Another way for the applicants to overcome the rejection is to persuasively argue that the claims contain elements in addition to the judicial exception that either individually or as an ordered combination are not well understood, routine, or conventional. Another way for the applicants to overcome the rejection is to persuasively argue that the claims as a whole result in an improvement to a technology. Persuasive evidence for an improvement to a technology could be a comparison of results of the claimed subject matter with results of the prior art, or arguments based on scientific reasoning that the claimed subject matter inherently results an improvement over the prior art. The applicants should show why the claims require the improvement in all embodiments.
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.
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.
Claims 1-5, 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al and Emens.
Claim 1 has been amended to provide a more detailed step of identifying alterations in DNA by RT mRNA in the cells and observing variations/mutations that may have occurred as a consequence of the chemotherapy, and an additional final step for synthesizing that has an alteration. Claim 1 requires only identification and now synthesis of possible variants that are identified. Given the teachings of both Liu et al and Emens that chemotherapy made the tumor more immunogenic, while neither specifically provide what changes made the cells more immunogenic, it would have been obvious to investigate the changes in a tumor cell, that is the proteins produced which made the tumor more immunogenic. Once particular antigens are identified, one could test the variant proteins to see if they provide the same synergistic affect before chemotherapy or in combination in other tumors as well.
Response to Applicants arguments
Applicants argue that Liu teach that there is cellular debris and is silent with respect to what is in the debris, and that DNA damage was what kill cancer cells.
In response, the affect of genotoxic agents was well known. It is agreed that generally chemotherapy that is genotoxic was provided to damage the DNA is amounts that would or could kill the cancer cell. However, as observed by both Liu et al. and Emens, there was also an additional synergistic affect and an increased tumor immunity (Emens provided that chemotherapy and tumor immunity showed an unexpected collaboration or synergy in the effects of the chemotherapy making the cancer cells more immunogenic.) It is noted that changes in proteins encoded by mutated DNA might be expected, and would be the basis of examining more specifically which proteins are made and altered that contributed to the increase immunogenic response. Claim 1 does not require that the protein identified is a successful target antigen for a vaccine, and the art of record does not suggest that all variants would necessarily serve this role either. Given the observation of both Liu et al and Emens, there is adequate expectation of success that one could observe changes in a cell after chemotherapeutic, more specifically once genotoxic compounds are provided to a cell and mutations occur, one could observe the changes by analyzing the genome or the mRNA which produces the altered proteins.
Therefore, for the reasons above and of record, the rejection is maintained. The basis of the rejection is provided below for completeness of the record.
The method of claim 1 requires treating cancer cells with an agent that damages DNA, then evaluating treated and untreated cancer cell sequences of possible open reading frames and providing for variants that could encode a variant protein after damaging the DNA. The function of some chemotherapeutic agents were well known, where some like 5FU were an active area of research for alterations they had on the genome and use for treating cancer (see both references for overview). More specifically, it was recognized that part of the affect of DNA damaging agents was the production of new antigens in cancer cells as described by Liu et al. who demonstrate that pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours. Generally, no specific new antigens were investigated by it was recognized that DNA damage provided and promoted an adaptive immune response in treated cancer cells. Similarly, Emens provided that chemotherapy and tumor immunity showed an unexpected collaboration or synergy in the effects of the chemotherapy making the cancer cells more immunogenic. Liu et al investigated the effect of chemotherapy on immune function and explored the effect of supernatant derived from tumour cells exposed to chemotherapy. Liu et al summarize their findings and teach that the induction of an effective immune response could lead to the elimination of residual tumour. Noting while attempts to enhance the immune response have essentially been on vaccine basis, trying to induce a specific response against the tumour that numerous vaccine approaches have claimed to provide significant clinical benefits. However it is recognized that providing an antigen alone is not usually sufficient and that known barriers to effective vaccine therapy are generally assumed that ‘vaccine with something else’ is best. Similarly, Emens teach chemotherapy directly targets the transformed tumor cell, and has long been a key component of therapy for most early and advanced cancers, but its utility is ultimately limited by drug resistance pathways deeply embedded within the biology of the tumor cell itself. Emens concludes that accumulating data suggests that it will be imperative to combine active immunotherapy with chemotherapy in a rational fashion, capitalizing on additive or even synergistic activity. The mechanisms by which distinct chemotherapeutics can enhance vaccine-induced tumor immunity are highly disparate, and quite dependent on chemotherapy dose, schedule, and perhaps tumor burden. Careful preclinical modeling using the most clinical relevant murine models will be essential for designing the most informative clinical trials, ensuring that tumor vaccines are effectively integrated with standard cancer care to improve clinical outcomes.
While neither Liu nor Emens specifically characterize the immunogenic effect of chemotherapeutic agents, they both recognize that cancer vaccines and something else is necessary for effective treatment. Beyond claim 1ependent claims set forth the variant sequences represent multiple possible antigenic sites in a protein, the cells are human and comprise a mutated p53 (an oncogene important as a cell cycle checkpoint and in DNA repair when normal), and the possible use of identified sequences as possible targets or antigens that could serve as a vaccine. The art readily recognized that chemotherapeutic agents like 5FU damage DNA and as evidenced by Liu and Emens enhance the immunogenicity of the cancer cells to therapy. Given the evidence, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to investigate further which protein sequences served to enhance immunogenicity for possible antigen in cancer vaccines for possible treatment or pbetter understanding of cancer treatment. The art of cancer vaccines is clearly complex, but one having ordinary skill in the art would have recognized and been motivated to identify cancer antigens that could serve in the treatment of cancer. Knowing that many chemotherapeutic agents damage DNA, would cause mutations that would produce variant proteins and serve to enhance immunogenicity as demonstrated by Li and Emens, there would have been a reasonable expectation of success to identify altered genomic DNA and altered proteins which may serve as novel antigens that could be combined with other therapeutics in the treatment of cancer.
Thus, the claimed invention as a whole was clearly prima facie obvious.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Joseph T Woitach whose telephone number is (571)272-0739. The examiner can normally be reached Mon-Fri; 8:00-4:00.
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/Joseph Woitach/Primary Examiner, Art Unit 1687