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 .
DETAILED ACTION
Claim Status
Claims 1-2, 4, 7, 9, 12, 14, 16, 18, 26, 28, 30, 114, 123-124, 130, 133, 147, 160, 182 are pending and are considered on the merits.
Priority
This application is a 371 of PCT/US2022/070690 (filed on 02/17/2022), which claims benefits from provisional applications 63/267,421 (filed on 02/01/2022), 63/260,855 (filed on 09/02/2021), 63/260,409 (filed on 08/19/2021), 63/159,434 (filed on 03/10/2021) and 63/153,862 (filed on 02/25/2021). The priority claim of the instant application has been granted and the earliest benefit date is 02/25/2021 from the application 63/153,862.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/08/2023 and 04/23/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Rejections - 35 USC § 112(a)
(Written Description)
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 123-124, 130, 133 and 147 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Under the new Written Description Guidelines for antigen binding proteins molecules, the Examiner is directed to determine whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination: on 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been re-evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
SCOPE OF THE INVENTION
Dependent claim 123 encompasses a genus of recombinant vectors comprising the Vα region comprising CDR1α, CDR2α and CDR3α each individually comprising a plurality of sequences, or the Vα region comprising a plurality of sequences having 90% identity to a list of sequences, or the Vα region and Vβ region each individually comprising a plurality of sequences having 90% identity to a list of sequences.
Dependent claim 124 encompasses a genus of recombinant vectors comprising the Vβ region comprising CDR1β, CDR2β and CDR3β each individually comprising a plurality of sequences, or the Vβ region comprising a plurality of sequences having 90% identity to a list of sequences.
Dependent claim 130 encompasses a genus of recombinant vectors comprising the TCR alpha chain comprising a plurality of sequences having 90% identity to a list of sequences.
Dependent claim 133 encompasses a genus of recombinant vectors comprising the TCR beta chain comprising a plurality of sequences having 90% identity to a list of sequences.
Independent claim 147 encompasses a genus of polynucleotide comprising a plurality of sequences 75% identical to a list of sequences, or encoding an amino acid sequence having 90% identity to a list of sequences that comprise only a TCR beta chain (or only a TCR alpha chain) and an IL-15/IL-15Rα fusion protein.
However, the specification only discloses 80 exemplary TCRs set forth in Table 6 (see p. 50-170) that each comprise a set of CDR1α, CDR2α, CDR3α, CDR1β, CDR2β and CDR3β, each comprise a set of Vα region and Vβ region, and each comprise a set of TCR alpha chain and TCR beta chain. In other words, the disclosed TCR sequences each have a defined set of TCR alpha chain comprising defined CDR1α, CDR2α and CDR3α and TCR beta chain comprising defined CDR1β, CDR2β and CDR3β.
ACTUAL REDUCTION TO PRACTICE
As stated supra, the dependent claims and independent claim have a much broader scope compared to that is disclosed in the specification. Specifically, Applicant has disclosed in the specification TCR sequences each have a defined set of TCR alpha chain comprising defined CDR1α, CDR2α and CDR3α and TCR beta chain comprising defined CDR1β, CDR2β and CDR3β. Thus, Applicant fails to show actual reduction to practice the broad scope as being claimed.
DISCLOSURE OF STRUCTURE
The Applicant has provided TCR sequences each have a defined set of TCR alpha chain comprising defined CDR1α, CDR2α and CDR3α and TCR beta chain comprising defined CDR1β, CDR2β and CDR3β, with specified respective sequences. Certainly, a skilled artisan could identify the framework of a TCR and obtain TCR variants with mixed CDR1, 2 or 3, or mixed α chain and β chain, or TCRs having variable domains with 90% identity to the cited sequences. However, neither the specification nor the art indicate a relationship between the structure of the claimed genus of TCRs comprising mixed CDRs, mixed chains, mutated variable domains or mutated TCRs, and the ability to bind to specific antigens to treat diseases.
Furthermore, regarding a Vα or a Vβ having a sequence of 90% identity in claims 123-124, a TCR α chain or a TCR β chain having a sequence of 90% identity in claims 130 and 133, the scope of the claims does not commensurate with the enablement provided by the disclosure with regard to the extremely large number of variants broadly encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties (i.e., antigen specificity of the TCR in the instant claims), predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to 80 exemplary TCRs set forth in Table 6 (see p. 50-170) that each comprise a defined set of CDR1α, CDR2α, CDR3α, CDR1β, CDR2β and CDR3β, each comprise a defined set of Vα region and Vβ region, and each comprise a defined set of TCR alpha chain and TCR beta chain.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple mixed-and-matches, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass all modifications of any TCR, any Vα or Vβ, or any CDRs, because the specification does not establish: (A) regions of the protein structure which may be modified without effecting antigen specificity; (B) the general tolerance of CDRs, Vα or Vβ, or TCRs to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any CDRs, Vα or Vβ, or TCRs residues with an expectation of obtaining the desired biological function capable of binding to a target antigen to treat diseases, and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)).
Without sufficient guidance, determination of exact nature of the CDR variants or mutant sequences of Vα or Vβ, or TCRs having the desired antigen-binding characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731,8 USPQ2nd 1400 (Fed. Cir, 1988).
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned in above, the amino acid sequences of exemplary TCRs are provided. Accordingly, if the skilled artisan sought to generate the claimed genus of TCRs, they would first need to know which sequences in the TCR could be chosen to modify or combine and still be able to predictably produce a functional TCR. Hence, based on the new written description guidelines, the Examiner should conclude that the applicant was not in possession of the claimed genus of recombinant vectors or polynucleotide encoding TCRs that bind to a target antigen to treat diseases.
The breadth of the claims encompasses a genus of recombinant vectors or polynucleotide encoding TCRs with mixed CDRs, mixed variable regions or mixed alpha or beta chains, or with mutated variable regions or alpha or beta chains. The present specification provides no guidance nor description to any rational in choosing how to mix and match those domains, therefore the skilled artisan would not know what rational approach to take to make modifications with any predictable outcome on binding function. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of a larger genus of TCRs related to those individual species. Otherwise, the Written Description guidelines suggest that the applicant is entitled to only the species specifically recited as having this activity. Moreover, even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number” of species.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making the claimed invention is not well established. Although the mutagenesis and combination of amino acid sequences is routine and conventional, one of skill in the art would neither expect nor predict the appropriate functioning of binding to target antigens to treat diseases produced according to the claimed genus of TCRs as broadly as is claimed.
Post art Milighetti et al (bioRxiv doi: https://doi.org/10.1101/2024.05.24.595718; posted May 29, 2024. P. 1-51) evidences that “the six complementarity determining regions (CDRs) of the T cell receptor (TCR) form multiple contacts with cognate peptide and major histocompatibility complex, thus determining antigen specificity” (abstract). Milighetti identifies consistent intra and inter-chain CDR contact zones within TCRα/TCRβ chains and these interactions restrict TCRα/TCRβ pairing within epitope-specific repertoires (abstract, p. 8-9 for intra and inter-chain CDR contact zones, and p. 11-15 for quantification of constraints on the paired TCRαβ amino acid sequences recognizing a given antigen). Thus, Milighetti evidences that a defined set of CDR1β, CDR2β and CDR3β, in combination with a defined set of CDR1α, CDR2α and CDR3α (i.e., all six CDRs in the paired TCR α and β chains) are required to determine antigen specificity of the TCR.
Applicant has claimed a genus of TCRs, yet the specification has only disclosed exemplary TCRs that each have a defined set of CDR1β, CDR2β and CDR3β in combination with a defined set of CDR1α, CDR2α and CDR3α with binding function. Independent of how these specific sequences were arrived upon by Applicant, a TCR cannot have mixed CDRs or variable domains and predictably produce functional antigen binding capability. Because Applicant has no manner a priori to predict what mix and match can be done to make a functioning TCR, the genus of TCRs claimed by Applicant cannot be predictably made or used by the ordinary artisan.
CONCLUSION
Therefore, the examiner concludes that there is insufficient written description of the instantly claimed genus. Specifically, there is limited description of the structure-function relationship between the claimed genus of TCRs and their ability to produce functional binding capability to a target antigen to treat diseases, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the TCRs encompassed by the claimed genus.
Therefore, the specification fails to provide sufficient written description to inform a skilled artisan that inventors were in possession of the entire scope of the claimed invention.
(Scope of Enablement)
Claim 182 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of reducing severity or ameliorating symptoms of a cancer or an autoimmune disease or disorder expressing an antigen recognized by the TCR in claim 1 (Specification, [00253]), does not reasonably provide enablement for a method of preventing or curing any cancer or any autoimmune disease or disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
SCOPE OF THE INVENTION
The breadth of the claim encompasses a genus of method of treating, encompassing preventing or curing (see Specification, [00253]), all cancers or all autoimmune diseases or disorders by administering any cells comprising the recombinant vector of claim 1. However, the specification fails to describe the genus of methods for preventing or completely curing all cancers or all autoimmune diseases or disorders. The specification only discloses and provides guidance for a method of reducing severity or ameliorating symptoms of a cancer or an autoimmune disease or disorder related to an antigen recognized by the TCR in claim 1. Specifically, the specification discloses 80 exemplary TCRs set forth in Table 6 (see p. 50-170) that recognize mutated forms of p53, KRAS and EGFR.
ACTUAL REDUCTION TO PRACTICE
The specification does not provide guidance for or a working example for a method for treating, including preventing or completely curing, all cancers or all autoimmune diseases or disorders. The absence of working examples necessitates further experimentation. Therefore, the specification does not provide sufficient guidance on how to make and use the claimed genus of methods.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
In fact, the state of the art teaches that a method for treating, including preventing or completely curing, all cancers or all autoimmune diseases or disorders, is not a highly successful technique or has highly variable results.
The primary difficulty in using cells comprising the claimed recombinant vector for cancer prevention or curing lies in the inherent nature of tumor initiation. Cancer develops from a few normal cells that have acquired mutations, often appearing in small, scattered, dormant populations long before they form a detectable mass. A systemic, engineered immune cell comprising the claimed vector would need to recognize and disrupt every single one of these scattered precancerous cells in the entire body to prevent tumor formation, which is impossible with current knowledge of tumor specific antigens or tumor associated antigens. For example, He et al., (“TCR-T cell therapy for solid tumors: challenges and emerging solutions”. Front Pharmacol. 2025;16:1493346, p. 1-15) evidences that “very few peptide antigen targets have been shown to be both safe and efficacious for TCR-T immunotherapy” and “Not all people produce neoantigens in the same way, and even individuals with the same type of solid tumor have diverse tumor cells that express different antigens” (p. 6, last para “3.2 Multiple limitations of targets”). Note too that Applicants only claim an IL-15/IL-15Rα fusion protein to self-supply pro-inflammatory cytokines, but are not claiming any elements to improve tumor recognition (i.e., the claimed invention does not address these problems).
Moreover, not all cancers are created equal. For example, Pancreatic Ductal Adenocarcinoma (PDAC) is notorious for its extremely dense stroma and low vascularity, forming an almost impenetrable barrier that excludes nearly all systemically delivered therapeutic agents. Glioblastoma (GBM), the most aggressive brain tumor, is shielded by the blood-brain barrier (BBB), which prevents efficient delivery of immune cells from the blood to the tumor cells in the brain. Metastatic Melanoma presents a challenge due to its rapid and high mutation rate, which leads to immense heterogeneity; this allows the cancer to quickly evolve resistance to any single targeted therapy, often leading to rapid relapse even after an initial response. Thus, even if (assuming arguendo) prevention or curing could be established for one cancer initially, it would not be expected to work for another or for relapse (i.e., the art is highly unpredictable). In addition, no examples were given in the specification for preventing/treating PDAC, GBM, etc. Further, a person of ordinary skill would not expect treatment to work safely for these more difficult diseases either. For instance, there's no proof that the cytokine storm side effect caused by TCR-T cell therapy could be overcome by the claimed recombinant vectors comprising an exogenous IL-15/IL-15Rα cytokine (see e.g., He et al, p. 7, left col, para “3.4 Cytokinetic storm).
Finally, Applicants are broadly claiming the prevention or curing of all cancers and all autoimmune diseases or disorders, not just one or two specific cancers. However, "the more one claims, the more one must enable." See Amgen v. Sanofi, 143 S.Ct. 1243 (2023)). Accordingly, the claims are not enabled for the full breadth of what is being claimed. See Automotive Technologies Int'I, Inc. v. BMW of North America, Inc., 501 F.3d 1274, 185 (Fed. Cir. 2007) ('claims must be enabled to correspond to their scope,').
Since even the post-filing art after the effective filing date of the present application did not provide guidance for preventing or completely curing all cancers or all autoimmune diseases or disorders encompassed by the instant invention, it is incumbent upon the instant specification to do so. The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; … in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that the method for preventing or curing all cancers or all autoimmune diseases or disorders is prone to influence by multiple factors, and is highly unpredictable, and the specification does not provide ample guidance, one would be burdened with undue experimentation to use the claimed invention for treating, including preventing or completely curing, all cancers or all autoimmune diseases or disorders.
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to use the invention beyond the scope of a method of reducing severity or ameliorating symptoms of a cancer or an autoimmune disease or disorder expressing an antigen recognized by the TCR in claim 1.
Examiner’s comment
Based on the limited scope of a method of reducing severity or ameliorating symptoms of a cancer or an autoimmune disease or disorder expressing an antigen recognized by the TCR in claim 1, enabled by Applicant’s specification, the following prior art have been applied to make obvious this limited scope of method.
Claim Rejections - 35 USC § 103
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.
Claims 1-2, 4, 7, 9, 12, 14, 16, 18, 26, 28, 30, 114, 123-124, 130, 133, 147, 160, 182 are rejected under 35 U.S.C. 103 as being unpatentable over Rezvani et al., (WO 2020/106621 A1, cited in IDS 12/08/2023) in view of Deniger et al., (WO 2019/067243 A1, cited in IDS 12/08/2023) and Hurton et al., (Proc Natl Acad Sci U S A. 2016; 113(48): E7788-E7797, cited in IDS 12/08/2023).
With respect to claim 1, Rezvani teaches a modular polycistronic vector system for the genetic reprogramming of cells to express one or more antigen receptors (see e.g., abstract and Fig 1A in the cover page), thus teaches the preamble a recombinant vector comprising a polycistronic expression cassette.
Rezvani teaches expression cassettes included in vectors contain a eukaryotic transcriptional promoter operably linked to a protein-coding sequence (e.g., [0067]), thus teaches the polycistronic expression cassette comprises a transcriptional regulatory element (e.g., a promoter) operably linked to the protein-coding sequence (i.e., a polycistronic polynucleotide).
Rezvani teaches the polycistronic vector comprising at least three cistrons wherein at least one cistron encodes for at least one antigen receptor (e.g., reference claim 1) and the antigen receptor is a T cell receptor (TCR) (e.g., reference claim 18), the adjacent cistrons on the vector are separated by a 2A self cleavage site (e.g., reference claim 4), at least one cistron encodes for a membrane-bound cytokine (e.g., [0010] and reference claim 24) and the cytokine is interleukin 15 (IL-15, e.g., [0010] and reference claim 25). Thus, Rezvani teaches the polycistronic polynucleotide comprises a polynucleotide sequence encoding a TCR (related to a TCR alpha chain, a 2A element and a TCR beta chain recited in the instant claim 1 a, b and c), a 2A element between cistrons (thus teaches claim 1 d) and a membrane-bound IL-15 (related to an IL-15/IL-15Rα fusion protein recited in the instant claim 1 e).
However, although Rezvani teaches the TCR comprises TCR α and β chains each comprising a variable domain and a constant domain (e.g., [0097] and [00101]) and recognizing tumor antigens such as p53 (e.g., end of [00104] and [00112]), Rezvani is silent on the polynucleotide sequence having a form of a TCR alpha chain, a 2A element and a TCR beta chain recited in the instant claim 1 a, b and c.
Deniger teaches isolating and purifying TCR having antigenic specificity for mutant human p53 (e.g., abstract). Specifically, Deniger teaches an exemplary TCR named “4141-TCR1a2” recognizing p53 mutation R175H that comprises the sequence of reference SEQ ID NO: 587 (see [0350]), in which there are a TCR alpha chain, a 2A element and a TCR beta chain (see sequence in [0350] and description in [0349]). Deniger teaches the variable sequence is fused to the murine constant sequence and the reconstructed TCR alpha and TCR beta are linked by furin-flexible-P2A (RAKR-SGSG-ATNFSLLKQAGDVEENPGP) (e.g., [0241]). In summary, Deniger teaches the polynucleotide sequence encoding the TCR having a form of a TCR alpha chain comprising an alpha chain variable region and an alpha chain constant region, a 2A element, and a TCR beta chain comprising a beta chain variable region and a beta chain constant region, as recited in the instant claim 1 a, b and c.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector comprising a polynucleotide sequence encoding a TCR recognizing tumor antigens such as p53 disclosed by Rezvani, by choosing a polynucleotide sequence encoding the TCR recognizing p53 mutation R175H having a form of a TCR alpha chain comprising an alpha chain variable region and an alpha chain constant region, a 2A element, and a TCR beta chain comprising a beta chain variable region and a beta chain constant region as suggested by Deniger with a reasonable expectation of success. Since Rezvani aims to construct a vector comprising TCR recognizing tumor antigens such as p53 (e.g., end of [00104] and [00112]), and since Deniger reduces to practice a cancer reactive TCR recognizing p53 mutation R175H having a form of a TCR alpha chain, a 2A element, and a TCR beta chain in a construct (e.g., [0349]), one of ordinary skill in the art would have had a reason to choose the sequence suggested by Deniger to use in the vector of Rezvani in order to obtain a recombinant vector comprising a TCR reactive to tumor antigen p53 R175H mutation.
However, although Rezvani teaches a membrane-bound IL-15 (e.g., [0010] and reference claims 24-25), Rezvani is silent on an IL-15/IL-15Rα fusion protein recited in the instant claim 1 e.
Hurton teaches tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells (see e.g., title and abstract). Hurton teaches a membrane-bound chimeric IL-15 (mbIL15) comprising an IL-15 and IL-15Rα fusion protein (see e.g., Fig 1A diagram and supplemental page 2, para 1 Plasmid design “mbIL15”), related to the instant claim 1 e. Hurton teaches the mbIL15 CAR T cells yield improved T-cell persistence independent of CAR signaling, and achieve potent rejection of CD19+ leukemia. Long-lived T cells are CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possess a memory-like transcriptional profile (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vector comprising a polynucleotide sequence encoding a membrane-bound IL-15 disclosed by Rezvani, by choosing a polynucleotide sequence encoding a membrane-bound IL-15/IL-15Rα fusion protein suggested by Hurton with a reasonable expectation of success. Since Rezvani aims to co-utilize a TCR vector with IL-15 to promote the eradication of established tumors (e.g., [00105], also see membrane-bound IL-15 in [0010]), and since Hurton reduces to practice a membrane-bound IL-15/IL-15Rα fusion protein that augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells (e.g., title), one of ordinary skill in the art would have had a reason to choose the membrane-bound IL-15/IL-15Rα fusion protein suggested by Hurton to use in the vector of Rezvani in order to take advantage of the augmented antitumor activity and enriched stem-cell memory subset in tumor-specific T cells.
With respect to claim 2 directed to 2A elements, Rezvani teaches the 2A cleavage site comprises a P2A, T2A, E2A and/or F2A site (see reference claim 26).
With respect to claim 4 directed to the P2A element comprising the sequence of SEQ ID NO: 18, Rezvani teaches the P2A sequence (see [0065]) that is 100% identical to the instant SEQ ID NO: 18 (see below):
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With respect to claim 7 directed to the T2A element comprising the sequence of SEQ ID NO: 22, Rezvani teaches the T2A sequence (see [0065]) that is 100% identical to the instant SEQ ID NO: 22 (see below):
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With respect to claim 9 directed to the 2A element encoding a furin recognition site optionally comprising the sequence of SEQ ID NO: 2 (“RAKR”), Rezvani teaches other cleavage sites include furin cleave site ([0048]), and Deniger teaches the reconstructed TCR alpha and TCR beta are linked by furin-flexible-P2A (RAKR-SGSG-ATNFSLLKQAGDVEENPGP) (e.g., [0241]), thus both teach a furin recognition site and Deniger makes obvious the sequence of SEQ ID NO: 2 (“RAKR”).
With respect to claim 12 directed to the second polynucleotide (a 2A element) encoding the sequence of SEQ ID NO: 10, as stated supra, Rezvani teaches the P2A sequence (see [0065]) and a furin cleave site ([0048]), and Deniger teaches the linker of furin-flexible-P2A (RAKR-SGSG-ATNFSLLKQAGDVEENPGP) (e.g., [0241]). It is noted that Deniger’s furin-flexible-P2A sequence is 100% identical to the instant SEQ ID NO: 10 (see below):
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With respect to claim 14 directed to the fourth polynucleotide (a 2A element) encoding the sequence of SEQ ID NO: 12, as stated supra, Rezvani teaches the T2A sequence (see [0065]) and a furin cleave site ([0048]), and Deniger teaches the linker of furin-flexible-P2A comprising the furin-flexible sequence of RAKR-SGSG in combination with a 2A element (e.g., [0241]). It is noted that the furin-flexible-T2A sequence suggested by Deniger and Rezvani is 100% identical to the instant SEQ ID NO: 12 (see below). Thus, Rezvani in view of Deniger make obvious the instant SEQ ID NO: 12.
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With respect to claim 16 directed to the IL-15 comprising the sequence of SEQ ID NO: 76, Hurton teaches the mbIL15 construct fuses the human codon-optimized IL-15 cDNA sequence (NM_000585.4) to the full-length IL-15Rα cDNA sequence (NM_002189.3) via a 26 amino acid glycine-serine linker [SG3(SG4)3SG3SLQ] (supplemental page 2. Para 1 “mbIL15”). The mature human IL-15 encoded by NM_000585.4 is 100% identical to the instant SEQ ID NO: 76 (see below):
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With respect to claim 18 directed to the IL-15Rα comprising the sequence of SEQ ID NO: 78, Hurton’s IL-15Rα encoded by NM_002189.3 is 100% identical to the instant SEQ ID NO: 78 (see below):
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With respect to claim 26 directed to the Cα region comprising the sequence of SEQ ID NO: 41, as stated supra, Deniger teaches an exemplary TCR named “4141-TCR1a2” recognizing p53 mutation R175H that comprises the sequence of reference SEQ ID NO: 587 (see [0350] and description in [0349]), in which the first italicized region is the alpha chain constant region that is 100% identical to the instant SEQ ID NO: 41 (see below):
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With respect to claim 28 directed to the Cβ region comprising the sequence of SEQ ID NO: 50, Deniger teaches the second italicized region is the beta chain constant region (see [0350] and description in [0349]), that is 100% identical to the instant SEQ ID NO: 50 (see below). It is noted that the amino acid #57 “X” in SEQ ID NO: 50 is Ser (S) or Cys (C) (see specification, p. 48, Table 5, Row 1).
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With respect to claim 30 directed to the order of cistrons, Rezvani teaches exemplary order of cistrons in [0051], such as “suicide gene-2A-antigen receptor-2A-cytokine-2A reporter gene” (row 2, [0051]), which contains an order of “antigen receptor-2A-cytokine”. As stated supra, Deniger makes obvious the antigen receptor TCR has a form of a TCR alpha chain, a 2A element, and a TCR beta chain. Thus, Rezvani in view of Deniger make obvious an order in claim 30 (a) the first polynucleotide sequence encoding the TCR alpha chain, the second polynucleotide sequence comprising a 2A element, the third polynucleotide sequence encoding the TCR beta chain, the fourth polynucleotide sequence comprising a 2A element and the fifth polynucleotide sequence encoding a cytokine.
With respect to claim 114 directed to a sixth sequence comprising a 2A element and a seventh encoding a marker protein, as stated supra, Rezvani teaches exemplary “suicide gene-2A-antigen receptor-2A-cytokine-2A reporter gene” (row 2, [0051]), which contains a sixth sequence comprising a 2A element (i.e., the 2A after the cytokine) and a seventh sequence encoding a marker protein (i.e., the reporter gene).
With respect to claim 123 (c) directed to the Vα region comprising the sequence of SEQ ID NO: 1014, Deniger teaches the alpha chain variable region includes the sequence starting from the amino terminus and ending immediately prior to the start of the alpha chain constant region (see [0350] and description in [0349]), that is 100% identical to the instant SEQ ID NO: 1014 (see below):
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With respect to claim 124 (c) directed to the Vβ region comprising the sequence of SEQ ID NO: 2014, Deniger teaches the beta chain variable region includes the sequence starting immediately after the linker and ending immediately prior to the start of the beta chain constant region (see [0350] and description in [0349]), that is 100% identical to the instant SEQ ID NO: 2014 (see below):
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With respect to claim 130 directed to the TCR alpha chain comprising the sequence of SEQ ID NO: 1019, Deniger teaches the TCR alpha chain sequence from the 5’ end to the linker (see [0350] and description in [0349]), that is 100% identical to the instant SEQ ID NO: 1019 (see below):
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With respect to claim 133 directed to the TCR beta chain comprising the sequence of SEQ ID NO: 2020, Deniger teaches the TCR beta chain sequence from the linker to the 3’ end (see [0350] and description in [0349]), that is 100% identical to the instant SEQ ID NO: 2020 (see below):
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With respect to independent claim 147 directed to a polynucleotide encoding the sequence of SEQ ID NO: 161, the rejections of claims 1, 14, 16, 18, 28, 30, 124 and 133 are incorporated herein for the sake of concise prosecution. Thus, Rezvani in view of Deniger and Hurton make obvious a recombinant vector comprising, in 5’ to 3’ order, the first polynucleotide sequence encoding the TCR alpha chain, the second polynucleotide sequence comprising a 2A element, the third polynucleotide sequence encoding the TCR beta chain, the fourth polynucleotide sequence comprising a 2A element and the fifth polynucleotide sequence encoding a cytokine, which contains a polynucleotide sequence comprising a combination of the third polynucleotide sequence encoding the TCR beta chain, the fourth polynucleotide sequence comprising a 2A element and the fifth polynucleotide sequence encoding an IL-15/IL-15Rα fusion protein. Regarding the TCR beta chain, Deniger teaches the TCR beta chain sequence from the linker to the 3’ end (see [0350] and description in [0349], also see rejection of claim 133). Regarding the 2A element, Rezvani and Deniger make obvious a furin-flexible-T2A sequence that is 100% identical to the instant SEQ ID NO: 12 (see rejection of claim 14). Regarding an IL-15/IL-15Rα fusion protein, Hurton teaches the signal peptides for IL-15 and IL-15Rα were omitted and the IgE signal peptide (gb|AAB59424.1) was used for the mbIL15 fusion protein. The mbIL15 construct fuses the human codon-optimized IL-15 cDNA sequence (NM_000585.4) to the full-length IL-15Rα cDNA sequence (NM_002189.3) via a 26 amino acid glycine-serine linker [SG3(SG4)3SG3SLQ] (supplemental page 2. Para 1 “mbIL15”). Thus, Hurton teaches an IL-15/IL-15Rα fusion protein comprising the sequence of the IgE signal peptide (AAB59424.1)-mature IL-15 encoded by NM_000585.4-linker “SG3(SG4)3SG3SLQ”- IL-15Rα encoded by NM_002189.3. In summary, this polynucleotide sequence encodes an amino acid sequence comprising Deniger’s TCR beta chain sequence (from the linker to the 3’ end in [0350])- a furin-flexible-T2A sequence-Hurton’s IL-15/IL-15Rα fusion protein sequence. This amino acid sequence is 100% identical to the instant SEQ ID NO: 161 (see below). It is noted that the amino acid #57 “X” in SEQ ID NO: 161 is Ser (S) or Cys (C) (see specification, p. 186, Table 10A, Row 2).
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With respect to independent claim 160, the rejection of claim 1 is incorporated herein for the sake of concise prosecution. Thus, Rezvani in view of Deniger and Hurton make obvious a recombinant vector comprising a first cistron encoding an IL-15/IL-15Rα fusion protein, a second cistron encoding the TCR beta chain comprising a Vβ region and a Cβ region, and a third cistron encoding the TCR alpha chain comprising a Vα region and a Cα region. Rezvani teaches a population of immune cells, such as T cells, comprising the antigen receptor and cytokines (e.g., [00134]), thus teaches the population of cells are T cells.
Regarding the T cells comprising the percentage of the subset, Hurton teaches the IL-15/IL-15Rα fusion protein (i.e., mbIL15) promotes a stem-cell memory subset in tumor-specific T cells and the mbIL15-CAR T cells are CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possess a memory-like transcriptional profile (abstract). Hurton teaches CD45RA+CD45ROnegCD62L+CCR7+IL-7Rα+CD122+CD95+ are bona fide TSCM markers, and Hurton’s TSCM population of mbIL15-CAR T cells (CD45RA+CD45ROneg CCR7+CD122+CD95+) had exposure to IL-21– and IL-15–mediated signaling during ex vivo numeric expansion, and then only to IL-15 (in the form of mbIL15) signaling, during the 65-d antigen and cytokine withdrawal assay to generate AWD-mbIL15-CAR T cells (p. 7795, last para), and about 80% of the mbIL15-CAR T cells express CD62L (see Fig. 1F).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have expected that the T cells comprising the polycistronic expression cassette comprising a TCR and an IL-15/IL-15Rα fusion protein would likely comprise more than 5% CD45RA+CD45RO-CD62L+CD95+ cells because Hurton teaches the IL-15/IL-15Rα fusion protein promotes a stem-cell memory subset (i.e., CD45RA+CD45RO-CD62L+CD95+ cells) in tumor-specific T cells.
Furthermore, MPEP 2145 (II) states that “mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”, and “the fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. In instant case, since the T cells comprising a TCR and an IL-15/IL-15Rα fusion protein as suggested by Rezvani in view of Deniger and Hurton are obvious over the instantly claimed T cells, mere recognition of latent properties of the percentage of a subset of T cells in the prior art does not render nonobvious an otherwise known invention.
With respect to claim 182 directed to a method of treating cancer comprising administering a therapeutically effective amount of a population of cells comprising the vector of claim 1, Rezvani teaches the disclosure provides methods for therapy, including immunotherapy, comprising administering an effective amount of immune cells encompassed by the present disclosure that are engineered to express the modular vector system provided herein, and cancer or infection is treated by transfer of an immune cell population (e.g., [00139]).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Statutory Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...”. Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 1 is rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 60 of U.S. Patent Application 18/847,945. This is a statutory double patenting rejection.
The subject matter claimed in the instant application is fully disclosed in the referenced patent application as follows: the recombinant vector of cited application is the same invention as the recombinant vector of instant application. It is clear that all the elements of the cited application claim are to be found in the instant claim in the exact same claim language.
Since the instant application claim is claiming identical subject matter as cited application claim, said claims are not patentably distinct.
Provisional Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 4, 7, 9, 12, 14, 16, 18, 26, 28, 30, 114, 123-124, 130, 133, 147, 160, 182 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 60-63 of copending Application No. 18/847,945 in view of Rezvani et al., (WO 2020/106621 A1, cited in IDS 12/08/2023), Deniger et al., (WO 2019/067243 A1, cited in IDS 12/08/2023) and Hurton et al., (Proc Natl Acad Sci U S A. 2016; 113(48): E7788-E7797, cited in IDS 12/08/2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims 60-63 of ‘945 recite a recombinant vector comprising a polycistronic expression cassette comprising a transcriptional regulatory element operably linked to a polycistronic polynucleotide comprising sequences encoding a TCR alpha chain, a first 2A element, a TCR beta chain, a second 2A element and an IL-15/IL15Rα fusion protein (it is noted that reference claim 60 recites exact the same subject matter as instant claim 1), the first to the fifth sequence being in any order from 5’ to 3’ (reference claim 61, related to instant claim 30), the TCR alpha chain and beta chain comprise sequences in Tables 1-79 (reference claim 62), and a population of cells that comprises the recombinant vector of claim 60 (reference claim 63, related to instant claim 160).
However, the copending claims are silent on the 2A sequence cited in claims 2, 4, 7, 12 and 14, a furin recognition site in claim 9, the IL-15 or IL15Rα sequences in claims 16 and 18, the Cα or Cβ sequences in claims 26 and 28, a sixth and seventh polynucleotide sequence comprising a 2A element and a marker protein in claim 114, the Vα or Vβ sequences in claims 123 and 124, the TCR alpha and beta chain sequence in claims 130 and 133, a polynucleotide sequence encoding an amino acid sequence of SEQ ID NO: 161 in claim 147, the population of cells being T cells with more than 5% of a subset in claim 160, or a method of treating cancer in claim 182.
Rezvani teaches expression cassettes included in vectors contain a eukaryotic transcriptional promoter operably linked to a protein-coding sequence (e.g., [0067], similar to the polycistronic expression vector in reference claims). Rezvani teaches the 2A sequence cited in instant claims 2, 4 and 7, a furin recognition site in claim 9, and a sixth and seventh polynucleotide sequence comprising a 2A element and a marker protein (a reporter gene) in claim 114. Rezvani teaches T cells comprising the polycistronic expression vector, related to claim 160. Rezvani teaches a method of treating cancer by administering cells comprising the vector in claim 182. (See above).
Deniger teaches a TCR construct comprising TCR alpha chain and beta chain linked by a furin-flexible-P2A site, thus teaches the sequence in claim 12 and makes obvious a furin-flexible-T2A sequence (with Rezvani) in claim 14. Deniger teaches the Cα or Cβ sequences in claims 26 and 28, the Vα or Vβ sequences in claims 123 and 124, the TCR alpha and beta chain sequence in claims 130 and 133. (See above).
Hurton teaches a membrane-bound IL15/IL15Ra fusion protein that augments antitumor activity and promotes Tscm subset, thus suggests that the T cells comprising the recombinant vector would likely have had more than 5% CD45RA+CD45RO-CD62L+CD95+ Tscm subset in claim 160. Hurton teaches the IL-15 or IL15Rα sequences in claims 16 and 18. (See above).
The polynucleotide encoding the TCR beta chain, a furin-flexible-T2A sequence and an IL-15/IL15Rα fusion protein suggested by Deniger, Rezvani and Hurton, encodes the amino acid sequence of SEQ ID NO: 161 in claim 147. (See above).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the recombinant vector recited in the copending claims of ‘945, by choosing the 2A and furin sequences of Rezvani and Deniger, combining a 2A and a marker suggested by Rezvani, choosing T cells and using in a method of treating cancer as suggested by Rezvani, by choosing the TCR alpha chain and beta chain sequences suggested by Deniger, and choosing the IL15/IL15Ra fusion protein sequence suggested by Hurton with a reasonable expectation of success. Since Rezvani, Deniger and Hurton reduce to practice the respective sequences to use the recombinant vector in T cells for treating cancer, one of ordinary skill in the art would have had a reason to choose the sequences, T cells and to use in a method of treating cancer in order to obtain a functional polycistronic expression vector to transfect T cells to take advantage of the augmented antitumor activity and the enriched Tscm subset phenotype.
Since the instant application claims are obvious over cited application claims, in view of Rezvani, Deniger and Hurton, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Claims 1-2, 4, 7, 9, 12, 14, 16, 18, 26, 28, 30, 114, 123-124, 130, 133, 147, 160, 182 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 47-48 of copending Application No. 18/834,112 in view of Rezvani et al., (WO 2020/106621 A1, cited in IDS 12/08/2023), Deniger et al., (WO 2019/067243 A1, cited in IDS 12/08/2023) and Hurton et al., (Proc Natl Acad Sci U S A. 2016; 113(48): E7788-E7797, cited in IDS 12/08/2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims 47-48 of ‘112 recite a population of cells comprising a polycistronic expression cassette comprising a first cistron comprising a polynucleotide sequence encoding a fusion protein comprising an IL-15 and an IL-15Ra, a second cistron comprising a polynucleotide sequence encoding a TCR beta chain comprising a Vβ region and a Cβ region, and a third cistron comprising a polynucleotide sequence encoding a TCR alpha chain comprising a Vα region and a Cα region (reference claim 47, related to instant claim 160), the population of cells are T cells that comprise more than 5% CD45RA+CD45RO-CD62L+CD95+ (reference claim 48, related to instant claim 160).
However, the copending claims are silent on 2A elements separating the cistrons in claim 1, the 2A sequence cited in claims 2, 4, 7, 12 and 14, a furin recognition site in claim 9, the IL-15 or IL15Rα sequences in claims 16 and 18, the Cα or Cβ sequences in claims 26 and 28, the order of cistrons in claim 30, a sixth and seventh polynucleotide sequence comprising a 2A element and a marker protein in claim 114, the Vα or Vβ sequences in claims 123 and 124, the TCR alpha and beta chain sequence in claims 130 and 133, a polynucleotide sequence encoding an amino acid sequence of SEQ ID NO: 161 in claim 147, or a method of treating cancer in claim 182.
Rezvani teaches expression cassettes included in vectors contain a eukaryotic transcriptional promoter operably linked to a protein-coding sequence (e.g., [0067], similar to the polycistronic expression vector in reference claims). Rezvani teaches the cistrons are separated by 2A elements, related to claim 1, the 2A sequence cited in instant claims 2, 4 and 7, a furin recognition site in claim 9, the order of cistrons in claim 30, and a sixth and seventh polynucleotide sequence comprising a 2A element and a marker protein (a reporter gene) in claim 114. Rezvani teaches a method of treating cancer by administering T cells comprising the vector in claim 182. (See above).
Deniger teaches a TCR construct comprising TCR alpha chain and beta chain linked by a furin-flexible-P2A site, thus teaches the sequence in claim 12 and makes obvious a furin-flexible-T2A sequence (with Rezvani) in claim 14. Deniger teaches the Cα or Cβ sequences in claims 26 and 28, the Vα or Vβ sequences in claims 123 and 124, the TCR alpha and beta chain sequence in claims 130 and 133. (See above).
Hurton teaches a membrane-bound IL15/IL15Ra fusion protein that augments antitumor activity and promotes Tscm subset. Hurton teaches the IL-15 or IL15Rα sequences in claims 16 and 18. (See above).
The polynucleotide encoding the TCR beta chain, a furin-flexible-T2A sequence and an IL-15/IL15Rα fusion protein suggested by Deniger, Rezvani and Hurton, encodes the amino acid sequence of SEQ ID NO: 161 in claim 147. (See above).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the T cells comprising the polycistronic expression cassette recited in the copending claims of ‘112, by combining 2A elements separating cistrons suggested by Rezvani, choosing the 2A and furin sequences of Rezvani and Deniger, combining a 2A and a marker suggested by Rezvani, using the T cells in a method of treating cancer as suggested by Rezvani, by choosing the TCR alpha chain and beta chain sequences suggested by Deniger, and choosing the IL15/IL15Ra fusion protein sequence suggested by Hurton with a reasonable expectation of success. Since Rezvani, Deniger and Hurton reduce to practice the respective elements and sequences to use the T cells for treating cancer, one of ordinary skill in the art would have had a reason to combine the 2A elements, choose the sequences, and to use in a method of treating cancer in order to obtain a population of T cells comprising the functional polycistronic expression vector to take advantage of the augmented antitumor activity and the enriched Tscm subset phenotype.
Since the instant application claims are obvious over cited application claims, in view of Rezvani, Deniger and Hurton, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Conclusion
No claims are allowed.
Examiner Contact Information
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
Prosecution Insights