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 .
Claims 1-19 are pending.
The improper restriction mailed March 9, 2026 is hereby withdrawn.
REQUIREMENT FOR UNITY OF INVENTION
As provided in 37 CFR 1.475(a), a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”). Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
The determination whether a group of inventions is so linked as to form a single general inventive concept shall be made without regard to whether the inventions are claimed in separate claims or as alternatives within a single claim. See 37 CFR 1.475(e).
When Claims Are Directed to Multiple Categories of Inventions:
As provided in 37 CFR 1.475 (b), a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:
(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.
Otherwise, unity of invention might not be present. See 37 CFR 1.475 (c).
Restriction is required under 35 U.S.C. 121 and 372.
This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1.
In accordance with 37 CFR 1.499, applicant is required, in reply to this action, to elect a single invention to which the claims must be restricted.
Group I, claim 1, drawn to a neoantigen comprising a particular sequence identifiable by SEQ ID NO.
Group II. Claims 2-4, drawn to T cell receptor that recognizes a particular sequence identifiable by SEQ ID NO.
Group III. Claims 3-4, drawn to a T cell comprising a particular T cell receptor that recognizes a particular sequence identifiable by SEQ ID NO.
Group IV. Claims 5-13, drawn to a method of treating a particular cancer in a subject comprising administering to the subject a particular neoantigen, T cell receptor or T cell.
Group V. Claims 14-19, drawn to a method of screening for a neoantigen.
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
Groups I-V lack unity of invention because even though the inventions of these groups require the technical feature of a neoantigen comprising the amino acid sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7), this technical feature is not a special technical feature as it does not make a contribution over the prior art of WO2015057635 publication (published April 23, 2015; PTO 892).
The WO2015057635 publication teaches a wild type (WT) estrogen receptor isoform 1 (ESR1) comprising the claimed sequence YSMKCKNVVPLYDLL, which is identical to the claimed SEQ ID NO: 7, see sequence underline in Figure 2 below, in particular. The term “comprising” is open ended. It expands the neoantigen peptide YSMKCKNVVPLYDLL to include additional amino acids at both ends.
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Therefore, the technical feature that links the groups is not special, as it does not make a contribution over the prior art and unity of invention is lacking in the instant case.
Accordingly, Groups I-V are not so linked as to form a single general inventive concept and the restriction requirement is proper.
Species Election
This application contains claims directed to more than one species of the generic invention. These species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1.
The species are as follows:
A particular neoantigen identifiable by SEQ ID NO in claims 1 and 6;
A particular T cell identifiable in claim 4 and 5.
A particular type of cancer identifiable at p. 45 of the specification.
Should Applicant elected Group I or II, Applicant is further required to elect (A) a particular neoantigen identifiable by SEQ ID NO. For example, amino acid sequence of the neoantigen is YSMKCKNVVPLYDLL (SEQ ID NO:7).
Should Applicant elected Group III, Applicant is further required to elect (A) a particular neoantigen identifiable by SEQ ID NO and (B) a particular T cell. For example, the T cell is a CAR T cell.
Should Applicant elected Group IV, Applicant is further required to elect (A) a particular neoantigen identifiable by SEQ ID NO, (B) a particular T cell and (C) a particular type of cancer to be treated. For example, breast cancer.
Applicant is required, in reply to this action, to elect a single species to which the claims shall be restricted if no generic claim is finally held to be allowable. The reply must also identify the claims readable on the elected species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered non-responsive unless accompanied by an election.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which are written in dependent form or otherwise require all the limitations of an allowed generic claim. Currently, the following claims 1, 2, 3, 5, 6, 14 are generic.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species or invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention or species may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected invention or species.
Should applicant traverse on the ground that the inventions have unity of invention (37 CFR 1.475(a)), applicant must provide reasons in support thereof. Applicant may submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. Where such evidence or admission is provided by applicant, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103(a) of the other invention.
Applicant is reminded that upon the cancellation 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. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Election
Applicant's election with traverse of Group I (claims 1-4), that read on SEQ ID NO: 7 as the species of neoantigen and chimeric antigen receptor (CAR) T cell as the species of T cell, filed September 8, 2026, is acknowledged.
The traversal is on the grounds that the Office Action has not shown that a serious burden would be required to examine all of the claims. MPEP § 803 provides that "[i]f the search and examination of an entire application can be made without serious burden, the Examiner must examine it on the merits, even though it includes claims to distinct or independent inventions." (emphasis added). Thus, for a restriction requirement to be proper, the Examiner must satisfy the following two criteria: (1) the existence of independent and distinct inventions (35 U.S.C. § 121) and (2) the search and examination of the entire application cannot be made without serious burden. See MPEP § 803. For example, Applicant respectfully asserts that the Examiner has not shown that it would be a serious burden to search and examine Groups I and II together. In particular, any search for a method of treating a cancer by administering a neoantigen, or a T cell (e.g., a CAR T cell, a TIL, and/or a MIL) comprising a T cell receptor recognizing thereof (as identified herein as Group II) would necessarily be a search for the neoantigen (as identified herein as Group I). The Examiner has not provided any credible basis as to why such a search would create a serious burden.
Since little to no additional burden would be required, Applicant respectfully asserts that the Examiner should search and examine Groups I and II together. Indeed, it would be most efficient for the Examiner to keep them together. For at least these reasons, Group II should be rejoined with elected Group I.
Applicant respectfully reminds the Examiner that the present application is a 371 National Stage filing and thus unity of invention rules apply to the restriction. 37 C.F.R. § 1.475 provides that national stage applications shall relate to one invention or to a group of inventions so linked as to form a single general inventive concept. Such inventions possess unity of invention. Respectfully, the Examiner has misapplied the rules governing unity of invention with respect to categories of invention. Specifically, it is rule 37 C.F.R. § 1.475 that discusses the determination of unity of invention. In particular, 37 C.F.R. § 1.475(b) states that "claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations." (emphasis added).
Applicants note that elected Group I and Group II each fall under § 1.475(b)(2); and for this reason alone should be rejoined. For example, claim 5 (Group II) is a method of treatment comprising administering a neoantigen of Group I, or a T cell (e.g., a CAR T cell, a TIL, and/or a MIL) comprising a T cell receptor recognizing thereof.
The Examiner alleges the instant application contains claims directed to more than one species of generic invention.
(a) As required, Applicant further provisionally elects SEQ ID NO: 7 as a species of neoantigen sequence, with traverse. Among the claims encompassing provisionally elected Group I, claims 1-4 encompass this species election.
(b) As required, Applicant further provisionally elects chimeric antigen receptor (CAR) T cell as a species of T cell, with traverse. Among the claims encompassing provisionally elected Group I, claim 4 encompasses this species election.
A requirement for restriction is permissible if there is a patentable difference between the species as claimed and there would be a serious burden on the Examiner if restriction is not required. See MPEP § 808.01(a). Applicant asserts that the latter standard is not met and that examination of all species would not be a burden to the Examiner.
As discussed in 37 C.F.R. § 1.141(a), an application may claim a reasonable number of species within a claimed genus as long as at least one genus claim encompassing all of the species is patentable. The Examiner has indicated that specific neoantigen sequence and a specific T cell comprising the TCR recognizing the elected species of neoantigen must be elected. Applicant asserts that the elections herein are an appropriate application of 37 C.F.R. § 1.141, which is aimed at situations where there are unreasonable numbers of species claimed. Applicant respectfully asserts that the present genus of forty-two (42) neoantigen sequences and three (3) T cells, represents a finite number of species and thus Applicant should not be required in the present application to elect a species when Applicant has not claimed an unreasonable number of species.
For at least the above reasons, reconsideration or withdrawal of the restriction requirement is requested.
Applicant respectfully reminds the Examiner that, upon allowance of a generic claim, Applicant will be entitled to consideration of claims to additional species that depend from or otherwise require all limitations of an allowable generic claim as provided by 37 C.F.R. § 1.141.
Applicants’ traversal has been fully considered but is not deemed persuasive for the following reasons:
The instant application is a 35 U.S.C. § 371 filing, and MPEP§ 1893.03(d), which describes restriction practice for applications filed under this statute states the following: “Examiners are reminded that unity of invention (not restriction) practice is applicable in international applications (both Chapter I and II) and in national stage applications submitted under 35 U.S.C. § 371…When making a lack of unity of invention requirement, the examiner must (1) list the different groups of claims and (2) explain why each group lacks unity with each other group (i.e., why there is no single inventive concept) specifically describing the unique special technical feature in each group”. The Examiner is not required to demonstrate an undue search burden.
Further, when Claims Are Directed to Multiple Categories of Inventions:
As provided in 37 CFR 1.475(b), a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:
(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.
Otherwise, unity of invention might not be present. See 37 CFR 1.475(c).
37 CFR 1.475(d) states:
(d) If multiple products, processes of manufacture or uses are claimed, the first invention of the category first mentioned in the claims of the application and the first recited invention of each of the other categories related thereto will be considered as the main invention in the claims, see PCT Article 17(3)(a) and § 1.476(c).
Thus, one invention of each category is to be considered.
As stated above, Groups I-V lack unity of invention because even though the inventions of these groups require the technical feature of a neoantigen comprising the amino acid sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7), this technical feature is not a special technical feature as it does not make a contribution over the prior art of WO2015057635 publication (published April 23, 2015; PTO 892).
The WO2015057635 publication teaches a wild type (WT) estrogen receptor isoform 1 (ESR1) comprising the claimed sequence YSMKCKNVVPLYDLL, which is identical to the claimed SEQ ID NO: 7, see sequence underline in Figure 2 below, in particular. The term “comprising” is open ended. It expands the neoantigen peptide YSMKCKNVVPLYDLL to include additional amino acids at both ends.
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Therefore, the technical feature that links the groups is not special, as it does not make a contribution over the prior art and unity of invention is lacking in the instant case.
Because Applicant's inventions do not contribute a special technical feature when viewed overthe prior art, the inventions lack unity of invention.
Therefore, the requirement of Groups I-V is still deemed proper and is therefore made FINAL.
Contrary to applicant’s assertion that there would not be a serious burden on the Examiner, the different Groups of invention such as neoantigen (peptide), T cell receptor, and T cell are different products that have different structures. The neoantigens are linear peptides having different sequences whereas T cell receptors are heterodimer comprising alpha and beta polypeptide chains that bind to neoantigen in complex with MHC class II or MHC class I. The T cells such as chimeric antigen receptor (CAR) T cells are genetically engineered T cell comprising a single chain antibody (scFv) that binds to a particular neoantigen. The methods of treating different cancer, e.g., lymphoma, breast cancer etc., using different product, e.g., neoantigen, T cell receptor, or chimeric antigen receptor have different method steps and endpoint and affect different patient population. Thus they are not obvious variants of each other.
Applicants’ request rejoinder of the method of treating cancer of Group II (now Group IV) is acknowledged. However, no generic claims are allowable at this time.
In response to applicant’s assertion that the genus of forty-two (42) neoantigen sequences and three (3) T cells, represents a finite number of species, the neoantigen sequences are not obvious variant of each other based on the current record. There is an examination and search burden for these patentably distinct species due to their mutually exclusive characteristics. The species of neoantigens have different amino acid sequences. The species require a different field of search (e.g., searching different sequence, classes/subclasses or electronic resources, or employing different search queries); and/or the prior art applicable to one species would not likely be applicable to another species; and/or the species are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.
Applicant respectfully reminds the Examiner that, upon allowance of a generic claim, Applicant will be entitled to consideration of claims to additional species that depend from or otherwise require all limitations of an allowable generic claim as provided by 37 C.F.R. § 1.141.
Upon reconsideration in view of compact prosecution, Groups II and III have been rejoined with the elected Group I.
Claims 5-19 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-4, drawn to a neoantigen that read on (A) SEQ ID NO: 7 as the species of neoantigen, and (B) a chimeric antigen receptor (CAR) T cell as the species of T cell that recognizes for said neoantigen are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/142,567, filed January 28, 2021 and 63/144,642, filed February 2, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 28, 2023 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on July 28, 2023 are acceptable.
Specification
The amendment to the specification filed on July 28, 2023 has been entered.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
Claims 1-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Regarding claim 1, the claim recites “(SEQ ID NO: 7)…(SEQ ID NO: 48)” renders the claim indefinite because it is unclear whether the limitation(s) in the parenthesis are part of the claimed invention. See MPEP § 2173.05(d). Deleting the parenthesis would obviate this rejection.
Claims 2-4 are included in the rejection because they are dependent on rejected claim and do not correct the deficiency of the claim from which they depend.
Claim Rejections - 35 U.S.C. § 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.
Claim 1 is 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 1 recites a neoantigen comprising the sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7).
Thus, the claim is drawn to amino acid sequences which is product of nature. A sequence comparison of SEQ ID NO:7 and the native protein comprising SEQ ID NO: 12 of issued patent is shown below.
As evidenced by US Patent No. 6,236,946, the peptide comprises naturally occurring amino acids from human estrogen receptor.
Query Match 100.0%; Score 3141; Length 595;
Best Local Similarity 100.0%;
Matches 595; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MTMTLHTKASGMALLHQIQGNELEPLNRPQLKIPLERPLGEVYLDSSKPAVYNYPEGAAY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MTMTLHTKASGMALLHQIQGNELEPLNRPQLKIPLERPLGEVYLDSSKPAVYNYPEGAAY 60
Qy 61 EFNAAAAANAQVYGQTGLPYGPGSEAAAFGSNGLGGFPPLNSVSPSPLMLLHPPPQLSPF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EFNAAAAANAQVYGQTGLPYGPGSEAAAFGSNGLGGFPPLNSVSPSPLMLLHPPPQLSPF 120
Qy 121 LQPHGQQVPYYLENEPSGYTVREAGPPAFYRPNSDNRRQGGRERLASTNDKGSMAMESAK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LQPHGQQVPYYLENEPSGYTVREAGPPAFYRPNSDNRRQGGRERLASTNDKGSMAMESAK 180
Qy 181 ETRYCAVCNDYASGYHYGVWSCEGCKAFFKRSIQGHNDYMCPATNQCTIDKNRRKSCQAC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ETRYCAVCNDYASGYHYGVWSCEGCKAFFKRSIQGHNDYMCPATNQCTIDKNRRKSCQAC 240
Qy 241 RLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRDDGEGRGEVGSAGDMRAANLWPSPLMIKR 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 RLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRDDGEGRGEVGSAGDMRAANLWPSPLMIKR 300
Qy 301 SKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASMMGLLTNLADRELVHMINW 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASMMGLLTNLADRELVHMINW 360
Qy 361 AKRVPGFVDLTLHDQVHLLECAWLEILMIGLVWRSMEHPGKLLFAPNLLLDRNQGKCVEG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 AKRVPGFVDLTLHDQVHLLECAWLEILMIGLVWRSMEHPGKLLFAPNLLLDRNQGKCVEG 420
Qy 421 MVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLSSTLKSLEEKDHIHRVLD 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 MVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLSSTLKSLEEKDHIHRVLD 480
Qy 481 KITDTLIHLMAKAGLTLQQQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNVVPLYDLL 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 KITDTLIHLMAKAGLTLQQQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNVVPLYDLL 540
Qy 541 LEMLDAHRLHAPTSRGGASVEETDQSHLATAGSTSSHSLQKYYITGEAEGFPATV 595
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 LEMLDAHRLHAPTSRGGASVEETDQSHLATAGSTSSHSLQKYYITGEAEGFPATV 595
Thus, the claimed peptide does not sufficiently distinguish over peptides as they exist naturally because the claims do not particularly point out any non-naturally occurring differences between the claimed products and the naturally occurring products. When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the exception as a "product of nature". For example, the isolated DNA of Myriad and the primers of Ambry Genetics were described as products of nature by the courts. Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). As explained in those decisions, products of nature are considered to be an exception because they tie up the use of naturally occurring things, but they have been labeled as both laws of nature and natural phenomena. See MPEP 2106.04(b).
Further, the human intervention required by the claims is limited to isolating the natural CRS products into a composition. However, in Myriad, the Supreme Court made clear that not all changes in characteristics will rise to the level of a marked difference, e.g., the incidental changes resulting from isolation of a gene sequence are not enough to make the isolated gene markedly different. Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75. See MPEP 2106.04(c). Therefore, here, like Myriad, the neoantigen comprising an isolated natural product is not markedly different from the natural product itself because there is no difference in the neoantigen in its natural and isolated state. This judicial exception is not integrated into a practical application because there are no additional elements that could integrate the judicial exception. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-4 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.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses any neoantigen comprising the sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7, elected species), YSMKCKNVVPLSDLL (SEQ ID NO: 16), YSMKCKNVVPLNDLL (SEQ ID NO: 17), YSMKCKNVVPLCDLL (SEQ ID NO: 18), YSMKCKNVVPLDDLL (SEQ ID NO: 19), YSMKCKNVVPLYGLL (SEQ ID NO: 20), YSMKCKNVVPRYDLL (SEQ ID NO: 21), YSMKCKNVVPHYDLL (SEQ ID NO: 22), YSMKCKNVVPPYDLL (SEQ ID NO: 23), YSMKCKNVVPQYDLL (SEQ ID NO: 24), KNVVPLYDLLLEMLD (SEQ ID NO: 8), KNVVPLSDLLLEMLD (SEQ ID NO: 25), KNVVPLNDLLLEMLD (SEQ ID NO: 26), KNVVPLCDLLLEMLD (SEQ ID NO: 27), KNVVPLDDLLLEMLD (SEQ ID NO: 28), KNVVPLYGLLLEMLD (SEQ ID NO: 29), KNVVPRYDLLLEMLD (SEQ ID NO: 30), KNVVPHYDLLLEMLD (SEQ ID NO: 31), KNVVPPYDLLLEMLD (SEQ ID NO: 32), KNVVPQYDLLLEMLD (SEQ ID NO: 33), LYDLLLEMLDAHRLH (SEQ ID NO: 9), LSDLLLEMLDAHRLH (SEQ ID NO: 34), LNDLLLEMLDAHRLH (SEQ ID NO: 35), LCDLLLEMLDAHRLH (SEQ ID NO: 36), LDDLLLEMLDAHRLH (SEQ ID NO: 37), LYGLLLEMLDAHRLH (SEQ ID NO: 38), RYDLLLEMLDAHRLH (SEQ ID NO: 39), HYDLLLEMLDAHRLH (SEQ ID NO: 40), PYDLLLEMLDAHRLH (SEQ ID NO: 41), QYDLLLEMLDAHRLH (SEQ ID NO: 42), IILLNSGVYTFLSST (SEQ ID NO: 10), IILLNSGVYTFLPST (SEQ ID NO: 43). SGVYTFLSSTLKSLE (SEQ ID NO: 11), SGVYTFLPSTLKSLE (SEQ ID NO: 44), FLSSTLKSLEEKDHI (SEQ ID NO: 12), FLPSTLKSLEEKDHI (SEQ ID NO: 45), GFVDLTLHDQVHLLE (SEQ ID NO: 13), GFVDLTLHDQVHLLQ (SEQ ID NO: 46), TLHDQVHLLECAWLE (SEQ ID NO: 14), TLHDQVHLLQCAWLE (SEQ ID NO: 47), VHLLECAWLEILMIG (SEQ ID NO: 15), and/or VHLLQCAWLEILMIG (SEQ ID NO: 48).
Claim 2 encompasses any T cell receptor that recognizes for one or more of the neoantigens of claim 1.
Claim 3 encompasses any T cell comprising the TCR of claim 2.
Claim 4 encompasses the T cell of claim 3, wherein the T cell is a tumor infiltrating lymphocyte (TIL), chimeric antigen receptor (CAR) T cell (elected species), or marrow infiltrating lymphocyte (MIL).
The specification defines singular form of “a” as follow:
[0039] 38. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
The specification defines treating as follow:
[0174] 165. As mentioned above, the disclosed methods of treating, inhibiting, decreasing, reducing, ameliorating, and/or preventing a cancer and/or metastasis can be used to treat, inhibit, decrease, reduce, ameliorate and/or prevent any disease or condition where uncontrolled proliferation occurs, including cancers. A representative but non-limiting list of cancers that the disclosed compositions can be used to treat is the following: lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin's Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, lung cancers such as small cell lung cancer and non-small cell lung cancer, neuroblastoma/glioblastoma, ovarian cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon cancer, rectal cancer, prostatic cancer, or pancreatic cancer.
The specification defines the term “subject” as follow:
[0047] 46. The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.
The specification discloses sequential peptide library screening of native ER peptide:
[0192] 183. ESR1 is the gene encoding Er-a and 11 point mutations (or single amino acid changes) were found within the gene coding region of the ligand binding domain (L536R, L536H, L536P, L536Q, Y537S, Y537N, Y537C, Y537D, D538G, S463P, and E380Q), leaving the resulting ER-a translated protein to be activated without stimulation by a ligand. Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of estrogen, conferring resistance against several endocrine agents (see FIG. 8). In fact, most of the mutations were found to convey constitutive activity to levels approximating those achieved by hormone stimulation and are strongly associated with reduced efficacy and potency of estrogen-deprivation therapies such as aromatase inhibitors and some antagonists, namely tamoxifen. The studies highlighted that mutations that constitutively activate ERα without the need for hormone binding are frequently found in endocrine—therapy-resistant breast cancer metastases and are associated with poor patient outcomes. Resistance with these mutations is attributed mostly to reduced binding affinity due to changes in amino acid interactions that slightly alter the protein's conformation in one of three areas.
[0193] 184. As we had the ER-peptide library created, we used the mutated regions of the ER protein to generate a mutated-ER peptide library. By using the peptide screening methodology detailed above, we identified class II immunogenic sequences exhibiting point mutations to develop a DC—vaccine targeting neoantigens. This could provide an alternative treatment approach to those patients exhibiting resistance to endocrine therapies due to these mutations.
[0194] 185. From the 11 noted point mutations, we cross matched their locations within the class II sequences of the ER peptide library. From this, each point mutation was represented in three peptide sequences due to the 10-amino acid overlap between adjacent sequences within the library. This overlap helps to account for binding affinity within the MHC II open binding groove (Table 3) 186. From the 11 mutations, a peptide library of 33 peptides (three sequences per mutation) was created (Table 3). As a comparison, we also screened the corresponding native or un-mutated ER sequences side-by-side to see if the mutation induced an increase in Th1 response compared to the native sequence.
[0195] 187. Table 3: the point mutations are listed in the second column on the left. The next three columns indicate the exact location of each point mutation within the corresponding peptide sequence (highlighted), giving three sequences each representing a single point mutation. The difference is in the location of the point mutation, either towards the end, the middle, or at the beginning of the sequence to account for differences in binding affinity to the MHC II molecule upon antigen presentation.
[0196] 188. FIG. 9 represents the screening results for the point mutations occurring at aa537 in four healthy normal donor samples. On the x-axis, each mutation corresponds to three peptides. On the far right of the graph are the corresponding native ER peptides: p106, p107, p108 for comparison. The approximate fold-increase in IFN-γ production is indicated above each peptide with a significant increase in response (green). When comparing the point mutation in each of these three locations to the native ER peptides, the results show that the ER sequences were not immunogenic, but with these single amino acid changes, it caused the sequence to be immunogenic. Overall, the location of the point mutation within the sequence did not have a large effect on the immunogenicity of the sequence.
[0197] 189. FIG. 10 shows the point mutation occurring at aa538 in four healthy normal donor samples. This corresponded to native ER peptides p106, p107, and p108. The approximate fold-increase in IFN-γ production is indicated above each peptide with a significant increase in response (green). When comparing the point mutation in each of these three locations to the native ER peptides, the results show that the ER sequences were not immunogenic, but with this single amino acid change, it caused the sequence to be immunogenic. Overall, the location of the point mutation within the sequence did not have a large effect on the immunogenicity of the sequence.
[0198] 190. FIG. 11 shows the point mutations occurring at aa536 in four healthy normal donor samples. This corresponded to native ER peptides p106, p107, and p108. The approximate fold-increase in IFN-γ production is indicated above each peptide with a significant increase in response (green). Comparing the point mutation in each of these three locations to the native ER peptides, the results show that native ER sequences were not immunogenic, while several sequences exhibiting a point mutation were immunogenic in three of four donor samples. Overall, the location of the point mutation within the sequence did not have a large effect on the immunogenicity of the sequence.
[0199] 191. FIG. 12 shows the point mutation occurring at aa463 in four healthy normal donor samples. This corresponded to native ER peptides p91, p92, p93. The approximate fold-increase in IFN-γ production is indicated above each peptide with a significant increase in response (green). When comparing the point mutation in each of these three locations to the native ER peptide, the results show that the sequences containing the point mutation were largely not immunogenic. However, in two of four donors, there was a common and significant increase in IFN-γ production from the native ER peptides p91 and p93. We will be checking this response in more samples to determine if the increase in response was donor specific or was indicative of an immunogenic peptide candidate in the native ER peptide library.
[0200] 192. FIG. 13 shows the point mutation occurring at aa380 in four healthy normal donor samples. This corresponded to native ER peptides p74 and p75. The approximate fold-increase in IFN-γ production is indicated above each peptide with a significant increase in response (green). When comparing the point mutation in each of these three locations to the native ER peptides, the results show that the native ER sequences were not immunogenic; however, the mutated peptide sequences demonstrated a significant increase in IFN-γ production in three of four donors. ESR1 mutations most often found in patient include D538G, Y537S, Y537N, Y537C, E380Q, and L536R, with point mutation D538G being the most prevalent mutation.
[0201] 193. Next we looked at the effect of peptide pulse on breast tissue from healthy donors (FIG. 14), donors with ER′ breast cancer tissue (FIG. 14), and donors with ERpos breast cancer tissue (FIG. 15). The final in vitro screening step was then to do a reverse sensitization (FIG. 15), where the primed CD4 T cells are re-stimulated with immature dendritic cells pulsed with the full tumor antigen in question, or the full protein. This step is important to determine if the identified immunogenic epitope can be recognized by T-cells primed to only a small amino acid sequence apart of the much larger protein. The results are summarized in FIG. 16.
[0202] 194. Expanding the peptide list we examined peptide pulsing on breast tissue from healthy donors (FIG. 17), donors with ER′ breast cancer tissue (FIG. 18), and donors with ERpos breast cancer tissue (FIG. 19). FIG. 20 shows a chart of fold-increase in IFN-γ production across all four donors used in screening of the mutated ER peptide library (significant increases are indicated in green). The results demonstrate that sequences exhibiting point mutations are reproducibly immunogenic (red).
Thus, the specification discloses neoantigen consisting of the amino acid sequence of SEQ ID NO: 7-48. The term “comprising” is open ended. It expands the neoantigen peptide to include additional amino acids at both ends.
However, the specification does not disclose neoantigen comprising sequences of SEQ ID NO: 7 to 48. The term “and” in claim 1 suggests that the claimed neoantigen comprising SEQ ID NO: 7 fused to other neoantigen sequences.
Regarding T cell receptor that recognizes any one or more neoantigen sequence comprising SEQ ID NO: 7 (claim 2), the specification does not describe the structure, e.g., amino acid sequence of any T cell receptor that recognizes any and all neoantigen sequences of claim 1. The specification provided no details about which the T cell receptor that recognizes or binds to neoantigen comprising the sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7) in a way that distinguishes them from T cell receptor that do not bind to SEQ ID NO: 7 or binds to all sequences of SEQ ID NO: 7 to 48 in the context of the HLA alleles of the subject.
The specification does not describe a representative number of species of T cell receptors falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed T cell receptor that recognizes any one or more neoantigen sequences of claim 1.
Wilson (Expert Rev Proteomics 15(2): 1065-1077, 2018; PTO 892) teaches that one major obstacle limiting the broader application of neoepitope based therapies is the difficulty of selecting highly immunogenic neoepitopes among the wide array of presented non-immunogenic of the MHC-I processing and presentation pathway, as well as highlight key areas that contribute to the complexity of the associated MHC-I peptidome, see entire document, abstract, in particular.
Regarding chimeric antigen receptor (CAR) T cells (claims 3-4), a chimeric antigen receptors (CARs, also referred to as chimeric immunoreceptors, chimeric T cell receptors, artificial T cell receptors, or CAR T) are engineered receptors that confer arbitrary specificity (e.g. scFv antibody) to an immune effector cell (i.e., a T cell). Such receptors are referred to as “chimeric” because these receptors include components derived from different sources.
However, the specification does not describe the structure, e.g., amino acid sequence of heavy chain variable domain (VH) and the light chain variable domain (VL) of the genus of monoclonal antibody or scFv encompassed by the chimeric antigen receptor T cells that recognized any neoantigen sequence such as SEQ ID NO: 7 recited in claim 1. The T cell receptor in claim 2 and T cell such as tumor infiltrating lymphocyte (TIL), CAR T cell and narrow infiltrating lymphocyte (MIL) in claim 4 are reached through claims.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards (J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Gupta (Cancer Discov 11(5): 1024-1039, 2021; PTO 892) teaches a subset of tumor-specific somatic mutations can be translated into immunogenic and HLA-bound epitopes called neoantigens, which can induce the activation of helper and cytotoxic T lymphocytes. However, cancer immunoediting and immunosuppressive mechanisms often allow tumors to evade immune recognition. Recent evidence also suggests that the tumor neoantigen landscape extends beyond epitopes originating from nonsynonymous single-nucleotide variants in the coding exome.
Regarding tumor infiltrating T cells (TIL) or marrow infiltrating T (MIL) cells that recognizes SEQ ID NO: 7, the specification discloses the peptide of SEQ ID NO: 7 is recognized by just CD4+ T cells. The MHC class II pathway is primary presented by the peptide in antigen-presenting cells (APC) such as dendritic cells (DC).
However, tumor infiltrating T cells (TIL) and marrow infiltrating T (MIL) are CD8+ T cells that recognize peptide in the MHC class I pathway. The antigenic peptide in the MHC class I is about 8-12 amino acids in length. The antigen peptide in the MHC class II pathway is about 13 to 28 amino acids in length, see Figure 2 of Gupta at p. 1027. It is not clear any TIL and MIL recognize any neoantigen sequence such as SEQ ID NO: 7.
The state of the art is such that in vitro T cell receptor recognizing 15-mer neopeptides derived from ESR1 Y537S (NVVPLSDLLLEMLDA) and D538G (NVVPLYGLLLEMLDA), with minimal reactivity towards the corresponding ESR1 WT peptide (NVVPLYDLLLEMLDA) and does not kill tumor cells because the ESR1 Y537S neopeptide was not endogenously processed for presentation.
Shafer et al (Cytothearpy 26(3): 266-275, 2024; PTO 892) teaches incongruity between T cell receptor recognition of breast cancer hotspot mutations ESR1 Y537S and D538G following exogenous peptide loading versus endogenous antigen processing. Specifically, Shafer teaches a method of identify neopeptide-specific TCRs using single-cell RNA sequencing of one of the T cell lines following neopeptide stimulation. The identified six HLA-class I presented ERα WT peptides within the region (ERα 319 – 507). Critically, while we detected HLA-class I bound ESR1 Y537S peptides (PLSDLLLEML and SDLLLEML) from LCLs pulsed with ESR1 Y537S peptide, these neopeptides were not detected in LCLs that overexpressed ESR1 Y537S in the absence of peptide pulsing. These data indicate that ESR1 Y537S neopeptides are not endogenously processed by predominantly immunoproteasome expressing cells, at least in the context of the HLA class I alleles expressed by this LCL line (HLA-A*02:01, HLA-A*01:01, HLA-B*40:02, HLA-B*08:01, HLA-C*15:02, and HLA-C*07:01). Collectively, the data demonstrate that while ESR1 Y537S and D538G neopeptides are capable of binding to HLA molecules and eliciting potent T cell responses, these peptides are not endogenously processed, ultimately rendering them non-immunogenic in a physiologically relevant sense, see entire document, p. 272.
Since the T cell receptor and chimeric antigen receptor are not adequately described, it follows that the method of treating any and all potential cancer by administering said T cell receptor or chimeric antigen receptor or T cell such as TILs MILs are not adequately described.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d, 2004 WL 260813, at 9 (Fed.Cir.Feb. 13, 2004). The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features that are common to the genus. That is, the specification provides neither a representative number of species that encompass the genus nor does it provide a description of structural features that are common to genus. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are 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.
Since the disclosure fails to describe common attributes or characteristics that identify members of the genus of T cell receptors, chimeric antigen receptor T cell, tumor infiltrating lymphocytes or marrow infiltrating lymphocyte (MIL), and because the genus is highly variant, the disclosure is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Although one of skill in the art could: make a mAb against an antigen/HLA class II complex, or screen a human antibody phage display library, test candidates, and produce a corresponding antibody, note that:
“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.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Further, mere listing of neoantigen to which a T cell receptor recognizes or binds, i.e., SEQ ID NO: 7 does not predict such T cell receptor or T cell is effective to treat any and all possible cancer in any and all mammalian subject, e.g., human, non-human primate, bovine, equine, porcine, canine, feline, guinea pig, rat, hamster, rabbit, mouse, or mole absence of any in vivo working example.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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).
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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only an isolated MHC class II-specific neoantigen consisting of the amino acid sequence selected from the group of SEQ ID NO: 7 to 24 and 28-48, (2) the isolated MHC class II-restricted neoantigen wherein the neoantigen is presented by antigen presenting cell (APC) and stimulates human CD4+ T cell in vitro, but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112, first paragraph.
Claims 1-4 are 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 (1) an isolated neoantigen consisting of the amino acid sequence selected from the group of SEQ ID NO: 7 to 24 and 28-48, (2) the isolated MHC class II-restricted neoantigen wherein the neoantigen is presented by antigen presenting cell (APC) and stimulates human CD4+ T cell in vitro, does not reasonably provide enablement for neoantigen comprising any sequence as set forth in claim 1, any T cell receptor that recognizes for any one or more of the neoantigen set forth in claim 2, any T cell such as chimeric antigen receptor (CAR) T cell as set forth in claims 3-4 for treating any and all cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any neoantigen comprising the sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7, elected species), YSMKCKNVVPLSDLL (SEQ ID NO: 16), YSMKCKNVVPLNDLL (SEQ ID NO: 17), YSMKCKNVVPLCDLL (SEQ ID NO: 18), YSMKCKNVVPLDDLL (SEQ ID NO: 19), YSMKCKNVVPLYGLL (SEQ ID NO: 20), YSMKCKNVVPRYDLL (SEQ ID NO: 21), YSMKCKNVVPHYDLL (SEQ ID NO: 22), YSMKCKNVVPPYDLL (SEQ ID NO: 23), YSMKCKNVVPQYDLL (SEQ ID NO: 24), KNVVPLYDLLLEMLD (SEQ ID NO: 8), KNVVPLSDLLLEMLD (SEQ ID NO: 25), KNVVPLNDLLLEMLD (SEQ ID NO: 26), KNVVPLCDLLLEMLD (SEQ ID NO: 27), KNVVPLDDLLLEMLD (SEQ ID NO: 28), KNVVPLYGLLLEMLD (SEQ ID NO: 29), KNVVPRYDLLLEMLD (SEQ ID NO: 30), KNVVPHYDLLLEMLD (SEQ ID NO: 31), KNVVPPYDLLLEMLD (SEQ ID NO: 32), KNVVPQYDLLLEMLD (SEQ ID NO: 33), LYDLLLEMLDAHRLH (SEQ ID NO: 9), LSDLLLEMLDAHRLH (SEQ ID NO: 34), LNDLLLEMLDAHRLH (SEQ ID NO: 35), LCDLLLEMLDAHRLH (SEQ ID NO: 36), LDDLLLEMLDAHRLH (SEQ ID NO: 37), LYGLLLEMLDAHRLH (SEQ ID NO: 38), RYDLLLEMLDAHRLH (SEQ ID NO: 39), HYDLLLEMLDAHRLH (SEQ ID NO: 40), PYDLLLEMLDAHRLH (SEQ ID NO: 41), QYDLLLEMLDAHRLH (SEQ ID NO: 42), IILLNSGVYTFLSST (SEQ ID NO: 10), IILLNSGVYTFLPST (SEQ ID NO: 43). SGVYTFLSSTLKSLE (SEQ ID NO: 11), SGVYTFLPSTLKSLE (SEQ ID NO: 44), FLSSTLKSLEEKDHI (SEQ ID NO: 12), FLPSTLKSLEEKDHI (SEQ ID NO: 45), GFVDLTLHDQVHLLE (SEQ ID NO: 13), GFVDLTLHDQVHLLQ (SEQ ID NO: 46), TLHDQVHLLECAWLE (SEQ ID NO: 14), TLHDQVHLLQCAWLE (SEQ ID NO: 47), VHLLECAWLEILMIG (SEQ ID NO: 15), and/or VHLLQCAWLEILMIG (SEQ ID NO: 48).
Claim 2 encompasses any T cell receptor that recognizes for one or more of the neoantigens of claim 1.
Claim 3 encompasses any T cell comprising the TCR of claim 2.
Claim 4 encompasses the T cell of claim 3, wherein the T cell is a tumor infiltrating lymphocyte (TIL), chimeric antigen receptor (CAR) T cell (elected species), or marrow infiltrating lymphocyte (MIL).
The specification defines singular form of “a” as follow:
[0039] 38. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
The specification defines treating as follow:
[0174] 165. As mentioned above, the disclosed methods of treating, inhibiting, decreasing, reducing, ameliorating, and/or preventing a cancer and/or metastasis can be used to treat, inhibit, decrease, reduce, ameliorate and/or prevent any disease or condition where uncontrolled proliferation occurs, including cancers. A representative but non-limiting list of cancers that the disclosed compositions can be used to treat is the following: lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin's Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, lung cancers such as small cell lung cancer and non-small cell lung cancer, neuroblastoma/glioblastoma, ovarian cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon cancer, rectal cancer, prostatic cancer, or pancreatic cancer.
The specification defines the term “subject” as follow:
[0047] 46. The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.
What is disclosed by the specification, by contrast, is narrow in that it only shows actual reduction to practice of screening library and isolating neoantigen consisting of the amino acid sequence of SEQ ID NO: 7-48.
Thus, the specification discloses neoantigen consisting of the amino acid sequence of SEQ ID NO: 7-48. The term “comprising” is open ended. It expands the neoantigen peptide to include additional amino acids at both ends.
However, the specification does not teach neoantigen comprising sequences of SEQ ID NO: 7 to 48. The term “and” in claim 1 suggests that the claimed neoantigen comprising SEQ ID NO: 7 fused to other neoantigen sequences.
Regarding T cell receptor that recognizes any one or more neoantigen sequence comprising SEQ ID NO: 7 (claim 2), the specification does not teach the structure, e.g., amino acid sequence of any T cell receptor that recognizes any and all neoantigen sequences of claim 1. The specification provided no details about which the T cell receptor that recognizes or binds to neoantigen comprising the sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7) in a way that distinguishes them from T cell receptor that do not bind to SEQ ID NO: 7 or binds to all sequences of SEQ ID NO: 7 to 48 in the context of the HLA alleles of the subject. There is no objective evidence of any T cell receptors that recognize any one or more neoantigen sequences in the specification as filed.
Wilson (Expert Rev Proteomics 15(2): 1065-1077, 2018; PTO 892) teaches that one major obstacle limiting the broader application of neoepitope based therapies is the difficulty of selecting highly immunogenic neoepitopes among the wide array of presented non-immunogenic of the MHC-I processing and presentation pathway, as well as highlight key areas that contribute to the complexity of the associated MHC-I peptidome, see entire document, abstract, in particular.
Regarding chimeric antigen receptor (CAR) T cells (claims 3-4), a chimeric antigen receptors (CARs, also referred to as chimeric immunoreceptors, chimeric T cell receptors, artificial T cell receptors, or CAR T) are engineered receptors that confer arbitrary specificity (e.g. scFv antibody) to an immune effector cell (i.e., a T cell). Such receptors are referred to as “chimeric” because these receptors include components derived from different sources.
However, the specification does not teach the structure, e.g., amino acid sequence of heavy chain variable domain (VH) and the light chain variable domain (VL) of the genus of monoclonal antibody or scFv encompassed by the chimeric antigen receptor T cells that binds any neoantigen sequence such as SEQ ID NO: 7 recited in claim 1.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards (J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Gupta (Cancer Discov 11(5): 1024-1039, 2021; PTO 892) teaches a subset of tumor-specific somatic mutations can be translated into immunogenic and HLA-bound epitopes called neoantigens, which can induce the activation of helper and cytotoxic T lymphocytes. However, cancer immunoediting and immunosuppressive mechanisms often allow tumors to evade immune recognition. Recent evidence also suggests that the tumor neoantigen landscape extends beyond epitopes originating from nonsynonymous single-nucleotide variants in the coding exome.
Regarding tumor infiltrating T cells (TIL) or marrow infiltrating T (MIL) cells that recognizes neoantigen such as SEQ ID NO: 7, the specification discloses the peptide of SEQ ID NO: 7 is recognized by CD4+ T cells via the MHC class II pathway. The MHC class II pathway is primary presented by the peptide in antigen-presenting cells (APC) such as dendritic cells (DC).
However, tumor infiltrating T cells (TIL) or marrow infiltrating T (MIL) cells that recognize peptide in the MHC class I pathway. The antigenic peptide in the MHC class I is about 8-12 amino acids in length. However, the antigen peptide in the MHC class II pathway is about 13 to 28 amino acids in length, see Figure 2 of Gupta at p. 1027. It is not clear any TIL and MIL recognize any neoantigen sequence such as SEQ ID NO: 7.
The state of the art is such that in vitro T cell receptor recognizing 15-mer neopeptides derived from ESR1 Y537S (NVVPLSDLLLEMLDA) and D538G (NVVPLYGLLLEMLDA), with minimal reactivity towards the corresponding ESR1 WT peptide (NVVPLYDLLLEMLDA) and does not kill tumor cells because the ESR1 Y537S neopeptide was not endogenously processed.
Shafer et al (Cytothearpy 26(3): 266-275, 2024; PTO 892) teaches incongruity between T cell receptor recognition of breast cancer hotspot mutations ESR1 Y537S and D538G following exogenous peptide loading versus endogenous antigen processing. Specifically, Shafer teaches a method of identify neopeptide-specific TCRs using single-cell RNA sequencing of one of the T cell lines following neopeptide stimulation. The identified six HLA-class I presented ERα WT peptides within the region (ERα 319 – 507). Critically, while we detected HLA-class I bound ESR1 Y537S peptides (PLSDLLLEML and SDLLLEML) from LCLs pulsed with ESR1 Y537S peptide, these neopeptides were not detected in LCLs that overexpressed ESR1 Y537S in the absence of peptide pulsing. These data indicate that ESR1 Y537S neopeptides are not endogenously processed by predominantly immunoproteasome expressing cells, at least in the context of the HLA class I alleles expressed by this LCL line (HLA-A*02:01, HLA-A*01:01, HLA-B*40:02, HLA-B*08:01, HLA-C*15:02, and HLA-C*07:01). Collectively, the data demonstrate that while ESR1 Y537S and D538G neopeptides are capable of binding to HLA molecules and eliciting potent T cell responses, these peptides are not endogenously processed, ultimately rendering them non-immunogenic in a physiologically relevant sense, see entire document, p. 272.
Given the lack of any teachings and in vivo working examples, it is unpredictable which cancer can be treated with the claimed neoantigen or T cell receptor or T cell such as TIL, MIL or chimeric antigen receptor T cells.
As such, one skilled in the art would need to resort to undue experimentation in a complex and unpredictable field in order to determine how to perform the invention as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102 (a)(1) as being anticipated by WO2015057635 publication (published; PTO 892).
Claim 1 recites a neoantigen comprising the sequence YSMKCKNVVPLYDLL (SEQ ID NO: 7). The phrase “comprising” encompasses a protein comprising the sequence YSMKCKNVVPLYDLL or the peptide YSMKCKNVVPLYDL itself.
The WO2015057635 publication teaches a wild type (WT) estrogen receptor isoform 1 (ESR1) comprising the claimed sequence YSMKCKNVVPLYDLL, which is identical to the claimed SEQ ID NO: 7, see sequence underline in Figure 2 below, in particular.
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The reference also teaches the polypeptide comprising the claimed YSMKCKNVVPQYDLL (SQE ID NO: 24), see sequence MO_1031 L536Q above, in particular.
The reference also teaches the polypeptide comprising the claimed YSMKCKNVVPLNDLL (SEQ ID NO: 17), see sequence Y537N above, in particular.
Thus, the reference teachings anticipate the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102 (a)(2) as being anticipated by Juneja et al (US20170177954 application, claimed earliest priority to 62/607,148 filed February 18, 2017; PTO 892).
Claim 1 recites a neoantigen comprising the sequence KNVVPLSDLLLEMLD
(SEQ ID NO: 25), KNVVPLNDLLLEMLD (SEQ ID NO: 26) or KNVVPLCDLLLEMLD (SEQ ID NO: 27).
Juneja et al teaches a peptide consisting of the amino acid sequence KNVVPLSDLLLEMLD from estrogen receptor isoform 1 (ESR1), which is identical to the claimed SEQ ID NO: 25, see p. 17, Table 1, sequence underline below, in particular.
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Thus, the reference teachings anticipate the claimed invention.
Claims 1-4 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by WO2019126186 publication (published June 27, 2019; PTO 892).
Claim 1 recites a neoantigen comprising the sequence KNVVPLSDLLLEMLD (SEQ ID NO: 25). The phrase “comprising” encompasses a protein comprising the sequence KNVVPLSDLLLEMLD or the peptide KNVVPLSDLLLEMLD itself.
The WO2019126186 publication teaches the claimed neoantigen comprising the amino acid sequence KNVVPLSDLLLEMLD, which is identical to the claimed SEQ ID NO: 25.
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Regarding claim 2, WO2019126186 publication teaches a TCR of a CD4+ T cell binds to class II HLA-peptide complex, see p. 89, lines 1-2, in particular.
Regarding claims 3-4, WO2019126186 publication teaches T cell, e.g., cytotoxic T cells (e.g., CD8+) or helper T cells (CD4+) expressing an antigen recognizing receptor, e.g., TCR or chimeric antigen receptor (CAR) that binds one of the neoantigenic peptides, see 105, para. [0269], in particular.
Thus, the reference teachings anticipate the claimed invention.
Allowable Subject Matter
An isolated neoantigen consisting of the amino acid sequence of SEQ ID NO: 7 to 24 and 28-48 are free of prior art.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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