DETAILED ACTION
This Action is in response to the amendment filed on 10/03/2025.
Claims 1, 11, 25-26, 132, 138, 141-143, 146, 148-149, 151-166, 168-177 are pending and are addressed herein.
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 .
Claim Rejections - 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, 11, 25-26, 132, 138, 141-143, 146, 148-149, 151-166, 168-177 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 fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
To satisfy the written description requirement, MPEP §2163 states, in part “…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.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species 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 functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
Claim 1 is drawn to a mRNA cancer vaccine comprising: an mRNA having an open reading frame encoding 10-50 cancer antigen peptide epitopes arranged in a head-to-tail formation, wherein the cancer antigen peptide epitopes comprise an activating oncogene mutation peptide; wherein the activating oncogene mutation peptide comprises an amino acid sequence of a recurrent somatic cancer mutation in p53, a KRAS mutation, or a NRAS mutation; wherein the cancer antigen peptide epitopes are selected by a process comprising: (a) identifying neoepitopes that are expressed in a tumor sample from a subject but not expressed in a normal tissue of the subject; and (b) selecting, from the identified neoepitopes, cancer antigen peptide epitopes that lack self reactivity in the subject; wherein at least one of the cancer antigen peptide epitopes is an MHC class I epitope and at least one of the cancer antigen peptide epitopes is an MHC class II epitope; wherein at least two of the cancer antigen peptide epitopes comprise point mutations; and wherein the lipid nanoparticle comprises, on a molar basis, 20-60% ionizable amino lipid, 5-25% neutral lipid, 25-55% sterol and 0.5-15% PEG-modified lipid (emphasis added). Claims 11, 25-26, 132, 138, 141-143, 146, 148-149, 151-152, 174-177 depend on claim 1 and encompass the 10-50 cancer antigen peptide epitopes.
Claim 153 is an independent claim similar to claim 1 and is drawn to a mRNA cancer vaccine comprising a lipid nanoparticle and a mRNA that has a 5’-UTR, an open reading frame encoding 10-50 cancer antigen peptide epitopes arranged in a head-to-tail formation, a 3’-UTR, and a poly-A tail, wherein the mRNA comprises at least one chemical modification; wherein the cancer antigen peptide epitopes are selected by a process comprising: (a) identifying neoepitopes that are expressed in a tumor sample from a subject but not expressed in a normal tissue of the subject; (b) determining whether the neoepitopes include neoepitopes comprising any of a recurrent somatic mutation in p53, a KRAS mutation, or an NRAS mutation, and (c) selecting, from the identified neoepitopes, cancer antigen peptide epitopes that have the following characteristics: (i) the cancer antigen peptide epitopes are selected from the identified neoepitopes; (ii) the cancer antigen peptide epitopes lack self reactivity; and (iii) each cancer antigen peptide epitope contains at least one of the following types of mutations: an insertion, a deletion, a substitution, and a frameshift mutation; wherein, if the plurality of neoepitopes includes one or more neoepitopes comprising a recurrent somatic mutation in p53, a KRAS mutation, or a NRAS mutation, the selecting comprises selecting at least one of the one or more neoepitopes comprising the recurrent somatic mutation in p53, KRAS mutation, or NRAS mutation, wherein at least one of the cancer antigen peptide epitopes is a MHC class I epitope and at least one of the cancer antigen peptide epitopes is an MHC class II epitope; wherein each cancer antigen peptide epitope is 9-30 amino acids in length; and wherein the lipid nanoparticle comprises, one a molar basis, 20-60% ionizable amino lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% polyethylene glycol (PEG)-modified lipid, wherein the ionizable amino lipid comprises a compound of Formula (I) as indicated in the claim, or a salt thereof (emphasis added). Claims 154-166, 168-173 depend on claim 153 and encompass the 10-50 cancer antigen peptide epitopes.
Thus, all claims encompass a genus of cancer antigen peptide epitopes (also known as personalized antigens) which must first be identified before the cancer vaccine can be made.
It is noted that the specification discloses:
The RNA vaccines may include a ribonucleic acid (RNA) polynucleotide having an open reading frame encoding at least one cancer antigenic polypeptide or an immunogenic fragment thereof (e.g., an immunogenic fragment capable of inducing an immune response to cancer). Other embodiments include at least one ribonucleic acid (RNA) polynucleotide having an open reading frame encoding two or more antigens or epitopes capable of inducing an immune response to cancer. (See paragraph [0007] of U.S. 2019/0351040, the published application).
Personalized vaccines, for instance, may include RNA encoding for one or more known cancer antigens specific for the tumor or cancer antigens specific for each subject, referred to as neoepitopes or subject specific epitopes or antigens (referred to as personalized antigens). A “subject specific cancer antigen” is an antigen that has been identified as being expressed in a tumor of a particular patient. The subject specific cancer antigen may or may not be typically present in tumor samples generally. (See paragraph [0166] of U.S. 2019/0351040, the published application).
Thus, the claims encompass a genus of cancer antigen peptide epitopes (also known as personalized cancer antigens) that are antigens expressed in tumor cells of a particular patient, and are capable of inducing an immune response to cancer cells that express the antigen. That is, the claims are drawn to a mRNA cancer vaccine that requires 10-50 cancer antigen epitopes that are expressed in tumor cells of a subject.
Although the specification discloses several cancer antigen peptide epitopes previously known in the art (recurrent p53 mutants, KRAS mutants, HRAS mutants, and NRAS mutants), the narrow disclosure of a few known cancer antigens is not sufficient to adequately describe the genus of cancer antigen peptide epitopes encompassed by the claims – a genus which includes personalized cancer antigens specific to the subject for which the mRNA vaccine is designed to treat. Since the claims require cancer antigen peptide epitopes expressed in a tumor of a particular patient which have not yet been identified, the claims require, by necessity, antigens which must be empirically identified for each patient.
It is noted that although the specification fails to identify any specific personalized cancer antigens encompassed by the claims, the specification does provide guidance for identifying personalized cancer antigens (i.e., cancer antigen peptide epitopes of the claims) such as in paragraph [0167], which states:
Methods for generating personalized cancer vaccines generally involve identification of mutations, e.g., using deep nucleic acid or protein sequencing techniques, identification of neoepitopes, e.g., using application of validated peptide-MHC binding prediction algorithms or other analytical techniques to generate a set of candidate T cell epitopes that may bind to patient HLA alleles and are based on mutations present in tumors, optional demonstration of antigen-specific T cells against selected neoepitopes or demonstration that a candidate neoepitope is bound to HLA proteins on the tumor surface and development of the vaccine. The mRNA cancer vaccines of the invention may include multiple copies of a single neoepitope, multiple different neoepitopes based on a single type of mutation, i.e. point mutation, multiple different neoepitopes based on a variety of mutation types, neoepitopes and other antigens, such as tumor associated antigens or recall antigens.
The limited disclosure of the specification in view of the vast genus of cancer antigen peptide epitopes (personalized cancer antigens) encompassed by the claims does not adequately describe the entire genus of molecules encompassed by the claims.
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must 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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself.
Thus, one of skill at the time of the invention could not have concluded that Applicant was in possession of the genus of cancer antigen peptide epitopes (personalized cancer antigens) that is required by the claimed mRNA vaccine.
Response to Arguments
Applicant's arguments filed 10/03/2025 have been fully considered but they are not persuasive.
Applicants makes eight specific arguments in response to the written description rejection: (1) The written description requirement is a flexible, context-dependent inquiry, (2) The written description requirement does not demand either examples or an actual reduction to practice, (3) The skilled in the art can reasonably conclude from the specification that Applicant was in possession of the claimed mRNA cancer vaccines, (4) The present claims recites product-by-process language describing the cancer antigen peptide epitopes consistent with the written description requirement, (5) The present claims recite the relevant structural features of the cancer antigen peptide epitopes, (6) The skilled artisan would be able to identify the cancer antigen peptide epitopes by the steps recited in the claims in view of the specification, (7) The skilled in the art did not rely on specific amino acid sequences to describe tumor-specific antigens for personalized cancer vaccines, (8) Efficacy does not require every encoded cancer antigen peptide to be independently immunogenic.
The arguments have been fully considered but they are not persuasive. The claims are drawn to a mRNA cancer vaccine that requires 10-50 cancer antigen peptide epitopes. The independent claims explicitly require that the cancer antigen peptide epitopes are selected by a process comprising identifying neoepitopes that are expressed in a tumor sample from a subject but not expressed in normal tissue of the subject and then selecting those that lack self reactivity in the subject. Thus, the claims clearly encompass cancer antigen peptide epitopes which they do not possess and which explicitly require further experimentation to identify the cancer antigen peptide epitopes required by the claimed mRNA cancer vaccine. Regarding possession of the invention, it is noted that MPEP 2163.02 states:
Whenever the issue arises, the fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, inventor was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the inventor was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). (Emphasis added).
In this case, Applicant does not show that the inventor was in possession of the claimed invention because they have not sufficiently described the invention with all of its limitations – specifically, the cancer antigen peptide epitopes required by the claims have not been sufficiently described. Since the cancer antigen peptide epitopes have not been sufficiently described, the claimed mRNA cancer vaccine, as a whole, has not been sufficiently described and rejection under 35 U.S.C. 112(a) for lack of sufficient written description of the claimed invention is appropriate.
Although the written description requirement may be a flexible, context-dependent inquiry which does not necessarily demand either examples or an actual reduction to practice, the written description requirement does indicate that applicant must show that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations.
With respect to the assertion that MPEP 2113 supports the notion that product-by-process claim format was permitted to provide a mechanism for claiming subject matter where the product can only be defined the process steps by which the product is made, it is noted that MPEP 2113 states, “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product…” In this case, the process steps are for identification of the cancer antigen peptide epitopes that exist in the tumor cells, and do not imply any particular chemical structure to the epitopes. The assertion that the recitation that the epitopes “are expressed in a tumor sample from the subject but not expressed in anormal tissue of the subject” is a relevant structural feature of the recited cancer antigen peptide epitopes” is not persuasive because the expression pattern of the epitopes is not related to the chemical structure of the epitopes. Rather the recitation merely indicates where the epitopes may be found (and not found) without providing any guidance with respect to the chemical structure of the cancer antigen peptide epitopes.
The argument that the skilled artisan would be able to identify the cancer antigen peptide epitopes by the steps recited in the claims, in view of the specification, is not persuasive, because additional experimentation would be required in order to identify the cancer antigen peptide epitopes. As indicated above, the court and the Board have repeatedly held that an adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method (citations omitted).
The arguments that the skilled in the art did not rely on specific amino acid sequences to describe tumor-specific antigens for personalized cancer vaccines is not relevant to the written description issue in this case. Here, the claims are drawn to a mRNA cancer vaccine that requires the identification of cancer antigen peptide epitopes with the only guidance being that the epitopes are expressed in a tumor sample from the subject but not expressed in a normal tissue of the subject. The claimed mRNA cancer vaccine thus requires that the cancer antigen peptide epitopes must first be identified before the vaccine can be made. Thus, the claims are attempting to cast a wide net to capture all cancer antigen peptide epitopes which are expressed in a tumor sample from the subject but not expressed in a normal tissue of the subject.
In this case, the claims clearly encompass cancer antigen peptide epitopes wherein further experimentation is required in order to identify the cancer antigen peptide epitopes. Although the disclosure provides method steps for identifying cancer antigen peptide epitopes, the fact that further experimentation is required indicates that the written description requirement has not been met. Although the disclosure may have adequately described a method of making a mRNA cancer vaccine, since further experimentation is required to identify the cancer antigen peptide epitopes, the claimed mRNA cancer vaccine has not been adequately described and a rejection under 35 U.S.C 112(a) is appropriate.
Therefore, Applicants’ arguments are not persuasive and the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637