Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendments filed on 12/15/2022 is acknowledged.
Claims 1, 7-8, 10, 17, 23-26, 32, 38, 44-47, 49, 57, 60, and 64-65 are pending in the instant application.
Priority
This application is a 371 of PCT/US2020/066468, filed on 12/21/2020 which claims priority to the provisional application 62952800 filed on 12/23/2019.
Election/Restriction
Applicant’s election without traverse of Group I (claims 7-8) in the reply filed on 10/15/2025 is acknowledged.
Claims 1, 10, 17, 23-26, 32, 38, 44-47, 49, 57, 60, and 64-65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/15/2025.
Claim 7-8
Claims 7-8 are examined herein.
Information Disclosure Statement
The information disclosure statements (IDS) dated 12/15/2022, 1/18/2024, 4/5/2024, and 11/07/2024 comply with the provisions of 27 CFR 1.97, 1.98, and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Objections to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pg 53, para 4; 58, para 0148; pg 59, para 0150; pg 60; para 0152; pg 61, para 0154; pg 62, para 0156; pg 62; para 0157; pg 63, para 0158; pg 64, para 0160; and pg 166, para 0400. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Correction is required. See MPEP § 608.01(b).
Background
Shokat, the inventor, (doi: 10.1016/j.ccell.2022.07.005) teaches
“Oncogenic driver mutations, by contrast, are very common and are exclusively expressed in tumor cells but not normal tissues. However, the vast majority of mutant oncoproteins are intracellular and thus beyond the reach of antibody-based therapeutic modalities. Targeting oncogene-derived peptide fragments (neoantigens) presented by Class I Major Histocompatibility Complex (MHC-I) using T cell receptor-mimicking antibodies is a promising strategy. but it is challenging to identify antibodies specific for a single amino acid substitution in the context of a particular MHC-I (HLA) allele” (pg 3, para 1).
“KRAS G12C is one of the most prevalent oncogenic driver mutations in lung and colon cancer. (pg 3, para 3).
“Although MHC-I presentation of mutant K-Ras peptides has been observed in patients,
it remains unknown whether a covalently attached inhibitor will interfere with antigen processing and subsequent binding to MHC-I complexes.” (pg 4, para 2).
For the purpose of clearly separating MHC peptides/alleles from the peptides they present, the term “neoantigen” is used throughout this office action instead of applicant’s “peptide antigen” where possible.
The term “HLA” and “MHC” are used interchangeably throughout this office action, in accord with literature (and the inventor’s) conventions.
Claim Interpretation
In claims 7-8, Applicant appears to redefine the term “stabilizing” as being equivocal to “enhancing recognition by T cells”:
“bringing them into the visibility of T-cell surveillance… may increase the MHC presentation of peptide antigen ( e.g. a driver oncogene derived peptide) relative to the absence of the MHC-peptide antigen stabilizing compound” (pg 78, para 0210).
Objections to the Claims
Claim 7 lacks a conjunction between the two method steps (b) and (c).
Claim 8 lacks a conjunction between the two method steps (i) and (ii).
Correction is required. See MPEP § 608.01(m).
Claim Rejections – 35 USC § 112(b)
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 7-8 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7
Claim 7, step (a), refers to “detecting an MHC allele of an MHC protein”, wherein (i) it is unclear what is being detected; and (ii) it is unclear what purpose that serves since any MHC allele/protein is being referred to. Regarding (i) “MHC allele” refers to nucleotide sequence, whereas “MHC protein” refers to an amino acid sequence. Thus it is unclear how the MHC protein (amino acid sequence) can contain an MHC allele (a nucleotide sequence). Because it is impossible to satisfy this claim limitation to detect something that does not exist, this claim is rendered indefinite. Furthermore, methods that detect DNA are materially and systematically distinct from those that detect proteins. Regarding (ii), the detection of any MHC alleles/proteins fails to logically promote the method of treating cancer as most MHC alleles/proteins are healthy. Secondly, for the method to function, the MHC allele/protein must be known to interact with the selected oncogene referred to in step (b). As an evidentiary reference, Shokat (the inventor, doi: 10.1016/j.ccell.2022.07.005) teaches “We focused on two common MHC-I alleles, HLA-A*02:01 and HLA-A*03:01, for which K-Ras peptide epitopes containing the mutant cysteine have been reported in the Immune Epitope DataBase (IEDB)” (pg 4, para 2). Dependent claim 8 fails to cure these deficiencies, thus is also rendered indefinite.
Claim 8
Claim 8 is rendered indefinite because it assumes “MHC-peptide antigen stabilizing compounds” are both a known genus as described in claim 7, yet still require identification using the method in claim 8. Thus it is unclear how a category of compounds can both be known and unknown. One of skill in the art would not be apprised of when infringement occurred, (e.g. during drug discovery or during drug administration, or both?). Thus rendering this claim indefinite.
Claim Rejections – 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 7-8 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.
Claim 7,8
Claim 7 refers to “MHC-peptide antigen stabilizing compounds” wherein a search of the prior art shows that this is not a well-defined genus, and claim 8 requires them to be discovered. To meet the written description requirement, applicant must provide (i) a representative number of species, or (ii) the core structure required for a compound to possess the property of stabilizing the MHC-peptide interaction. Applicant provided an open definition describing this genus by function alone:
“In embodiments, an MHC-peptide antigen stabilizing compound increases the MHC presentation of driver oncogene derived peptides, bringing them into the visibility of T-cell surveillance. Thus, an MHC-peptide antigen stabilizing compound may increase the MHC presentation of peptide antigen ( e.g. a driver oncogene derived peptide) relative to the absence of the MHC-peptide antigen stabilizing compound. In embodiments, an MHC-peptide antigen stabilizing compound induces the presentation of KRAS (G12D) derived peptides by HLA-B*57:01. In embodiments, an MHC-peptide antigen stabilizing compound induced the presentation of KRAS (G12V) derived peptides by HLA-B*57:01. In embodiments, where the MHC presentation is increased or induced, the MHC-peptide antigen is stabilized by the MHC peptide antigen stabilizing compound relative to the absence of the MHC-peptide antigen stabilizing compound” (pg 78, para 0210).
The disclosure describes compounds that are effective in covalently modifying mutant K-Ras (called “KRAS (G12D)), wherein these neoantigens are presented by a single subtype of MHC called HLA-B*57:01. This sole exemplary category of “compounds that enhance T cell recognition” of one mutant oncogene paired with one MHC allele fails to describe the genus of all “MHC-peptide antigen stabilizing compounds”. While applicant has also described a chemical structure (pg 88, para 0254), one of skill in the art would have no reasonable expectation that all compounds of this form exhibit the property of enhancing MHC peptide presentation of any peptide, oncogenic or not. Dependent claim 8 fails to cure these deficiencies, thus is also fails the written description requirement.
Claim Rejections – 35 USC § 112(a) - Enablement
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 7-8 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 7,8
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention/Breadth of Claims:
Claim 7 is drawn to a method of treating cancer comprising detecting any MHC allele/protein, detecting any mutated oncogene, followed by administering any MHC-peptide antigen stabilizing compound. Claim 8 adds the contradictory method steps that require the structure of the “MHC-peptide antigen stabilizing compound” being both known and unknown to the skilled practitioner.
State of the prior art/Predictability or unpredictability of the art:
Osterov (doi: 10.1073/pnas.1207934109) teaches that small molecules can enhance T-cell receptor recognition of presented neoantigens by three different mechanisms: (1) neoantigen that is uniquely presented by the HLA is modified by the drug; (2) the HLA itself is modified in a region exposed to the TCR; or (3) the binding specificity of the HLA is altered by the presence of the drug, resulting in presentation of novel ligands such as peptide B. (pg 9960, Fig 1, reproduced below).
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Thus, at a minimum, the selected small molecule must target a particular neoantigen or HLA. Osterov teaches the drug, Abacavir, binds to HLA-B*5701 using the mechanism (3) (pg 9963, col 1, para 2). Osterov teaches “Together, these biochemical and structural findings provide an explanation for why, of the more than 5,000 class I MHC alleles, only HLA-B*5701 is affected by abacavir.” Thus the structure of the MHC allele of the individual determines whether or not the particular drug chosen has an effect.
Amount of guidance/Existence of working examples:
The disclosure describes compounds that are effective in covalently modifying mutant K-Ras (called “KRAS (G12D)), wherein these neoantigens are presented by a single subtype of MHC called HLA-B*57:01. Essentially, applicant has provided one mutant oncogene (KRAS (G12D)) with one MHC allele (HLA-B*57:01), for which the compounds of the invention are effective in enhancing T cell stimulation. Note, this is the same MHC allele described by Osterov, and applicant is claiming related Abacavir analogues (Exemplary species reproduced below from instant claim 44, line 17).
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Quantity of experimentation:
Given
The specificity the drug must possess to the particular HLA allele/protein and/or the neoantigen in order to function (as described by Osterov); and
The absence of any examples excluding Abacavir analogues that bind the HLA-B*57:01 allele/protein that enhance the detection of neoantigens produced by the exemplary oncogene KRAS (G12D),
one of skill in the art would have no reasonable expectation of success in treating cancer using the method described. The method’s absence of specificity on the particular HLA, neoantigen, and compound structure would require a person of skill in the art undue experimentation to identify which combination of these immensely diverse variables would yield an effective anti-cancer treatment. While applicant has described exemplary compounds with the desired function, they were not obtained using the method described, nor were they described in the instantly claimed method. In generating the functional compounds of the invention, Applicant selected a known HLA/MHC, they did not “detect” a random HLA/MHC allele in an individual; nor did they “detect” a random oncogene in an individual, they screened compounds that specifically enhanced K-Ras neoantigen presentation (Example 1), wherein K-Ras was a known commonly mutated protein in cancer (see “Sun” in “Relevant Prior Art” section). It is evident from the disclosure, that the task of identifying working “MHC-peptide antigen stabilizing compounds” for a particular HLA allele/protein and neoantigen requires substantial experimentation (e.g. crystal structure determination of prototype drugs within the HLA pocket when bound to the particular neoantigen to identify the structure-function relationship to inform design of functional small molecule analogues (see Osterov, Fig 3).)
Lack of a working example is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP § 2164.
See the decision in Rasmusson v. SmithKline 413 F.3d 1318, 1325 (Fed. Cir. 2005) which stated: “Thus, at the end of the day, the specification, even read in the light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient. [Citation omitted.] ‘If mere plausibility were the test for enablement under §112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the “inventor” would be rewarded the spoils instead of the party who demonstrated that the method actually worked.’”
Therefore, in view of the Wands factors as discussed above, e.g., the amount of guidance provided, the predictability of the art and the lack of working examples, to practice the full scope of the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Relevant Prior Art
Sun et al. (doi: 10.1002/anie.201201358) teaches that K-Ras is a small GTPase that is commonly mutated into a hyper-activate state in 30% of cancers (pg 6140, para 1). Sun teaches downregulation of K-Ras results in dramatic regression of tumors, thus therapeutic strategies to inhibit oncogenic forms of K-Ras are thus targeted for treating cancer (pg 6140, para 1). Sun teaches molecules featuring the substructures below bind mutant K-Ras, called K-Ras (G12D) (Scheme 1, reproduced below).
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Long et al. (CN103864764A) describes indazole-substituted pyrimidine derivatives of the structure below that are useful in treating cancer (abstract), such as compound 3.
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Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA ANN ESSEX whose telephone number is 571-272-1103. The examiner can normally be reached Mon - Fri 8:30-5:00.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/
Supervisory Patent Examiner, Art Unit 1675