DETAILED ACTION
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 .
Priority
The instant application is a 371 National Stage Entry of PCT/US2022/082136 filed on December 21, 2022 which claims benefit to domestic provisional application Nos. 63/322,528 filed on March 22, 2022; 63/313,040 filed on February 23, 2022; and 63/292,910 filed on December 22, 2021.
Status of Claims
Acknowledgement is made of original (1), amended (13, 43, 76-77, 79-82, 88, 94, 100, 106, 112), cancelled (2-12, 14-42, 51-75, 78, 83-87, 89-93, 95-99, 101-105, 107-111, 113-117), and new (118-129) claims filed on January 10, 2025. Claims 1, 13, 43, 76-77, 79-82, 88, 94, 100, 106, 112, 118-129 are pending in instant application.
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 1, 13, 43, 76-77, 79-82, 88, 94, 100, 106, 112, 118-129 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.
While the specification provides narrowed subcategories of Switch II Pocket inhibitors and lists specific examples such as compounds 1’-5’ and 1-7 (see instant spec. at Figures 2A and 3A for compounds 1’-5’ and at Figures 19A, 26A, 29A for compounds 1-7), the disclosure does not demonstrate possession of the full scope of the claimed subject matter.
Instant Disclosure
Instant Claim 1
β-lactones, β-lactams
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K-Ras(G12S)
Switch II GTPase Protein
Instant Disclosure
Instant Claim 118
β-lactones, β-lactams
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K-Ras(G12D)
Switch II GTPase Protein
Instant Disclosure
Instant Claims 79-82, 88, 94,
100, 106, 112, 121-129
K-Ras(G12S), K-Ras(G12D)
K-Ras, N-Ras, H-Ras
A K-Ras(G12S) or K-Ras(G12D) associated disease selected from cancer or a RAS-opathy
Cancer
The instant R1 “Switch II Binding Pocket moiety” is defined as a moiety of a compound that binds to the Switch II Binding Pocket (see instant spec. at p. 61 ¶[0202]).
The instant L1 linker is defined as a bond or divalent moiety.
The instant E2 is an electrophilic moiety capable of forming a covalent bond with a Switch II GTPase protein aspartate residue of a Switch II GTPase protein glutamate residue (see claim 1).
The instant E1 is an electrophilic moiety capable of forming a covalent bond with a Switch II GTPase protein serine residue of a Switch II GTPase protein threonine residue (see claim 118).
Accordingly, instant claims 1, 43, and 118 recite no tangible structure, and are entirely defined by what the genus does (R1 binds to Switch II Binding Pocket, E1 or E2 is capable of binding to a Switch II GTPase protein residue, and L connects the two), not what it is.
The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. 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 species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
A description of a chemical genus will usually comprise a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the members of the genus. See Univ. of California vs. Eli Lilly, 43 USPQ 2d 1398, 1406 (Fed. Cir. 1997). This is analogous to enablement of a genus under section 112 first, by showing enablement of a representative number of species within the genus. A chemical genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance, the disclosure must describe a sufficient number of species to reflect the variation within that genus.
Applicant has failed to show that they were in possession of most of the diverse compounds encompassed by general formula I, II, III, IV, V, or VI. Applicant discloses the specific structures of a very narrow set of compounds (see instant spec. at pp. 164-188). Moreover, the specific structures of the very narrow set of compounds (see id) contain very narrow set of options for E1 or E2, L, and R1 despite claiming that the groups can be anything with the indicated function without specifying or limiting the type of structure.
For example, in Applicant’s disclosed species embodiments:
L appears to only ever be a bond or methylene.
E1 or E2 is always a β-lactone or β-lactam. No instances of X as S or Y as S are provided (compare claim 13 with instant spec. at pp. 164-188 species).
E1, when bound to mutant K-Ras, is only ever bound to an aspartate 12 residue (see instant spec. at pp. 358-363).
E2, when bound to mutant K-Ras, is only ever bound to a serine 12 residue (see instant spec. at pp. 319-324).
R1 appears to always be selected from the structural options of claim 50 (see species in instant spec. at instant spec. at pp. 164-188).
This small set of compounds cannot be viewed as being reasonably representative of the genus in its claimed scope because no readily apparent combination of identifying characteristics is provided, other than the disclosure of those specific species as examples of the claimed genus.
The use of a method of:
i) treating any diseases associated with K-Ras, N-Ras, or H-Ras (claims 79-81, 121-123),
ii) modulating the level of activity of K-Ras, N-Ras, or H-Ras (claims 82, 88, 94, 124-126),
iii) covalently binding the compound to a serine residue of K-Ras, H-Ras, or N-Ras (claims 100, 106, 112, 127-129)
with the compounds of Formulas I, II, III, IV, V, or VI encompassed additional, undefined methods beyond those described. The specification does not provide sufficient details, representative examples, or common principles to support the breadth of such an open-ended genus. For example, details such as what moieties or compounds of the instant Formula are capable of binding to K-Ras vs H-Ras vs N-Ras, what compounds are capable of binding to threonine or glutamate residues in K-Ras, H-Ras, or N-Ras, what compounds of the instant Formulas are suitable for what diseases, or dosage regimens and schedules – details necessary for treating diseases not included by Applicant’s disclosure.
A person of ordinary skill in the art would thus not reasonably conclude that Applicant was in possession of the entire scope of:
i) the instantly claimed compounds of Formula I-IV and compositions comprising (claims 1, 13, 43, 76, 118-119),
ii) the instantly claimed conjugates bound to a protein residue (claims 100, 106, 112, 127, 128, 129),
ii) the methods of treating (79, 80, 81, 120, 121, 122, 123), or
iii) the methods of modulating (82, 88, 94, 124-126).
Suggested Amendment
The Examiner suggests amending the independent compound claims to structurally defined common cores disclosed by Applicant. For example, limiting the structural limitations of E1 or E2 to those listed in claim 13, limiting the structural limitations of R1 to those listed in claim 50, limiting the structural limitations of L to a bond or alkylene, limiting X to O, limiting Y to O or N, encompassing all these limitations into both independent claims 1 and 118, and cancelling claims 13, 43, 50.
See also the 112(a) Scope of Enablement below for further amendment suggestions regarding the methods and conjugates claims.
Claim Rejections - 35 USC § 112(a) – Scope of 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 1, 13, 43, 76-77, 79-82, 88, 94, 100, 106, 112, 118-129 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 using disclosed compound species for I) treating a K-Ras(G12D)-associated or K-Ras(G12S)-associated disease selected from cancer and RASopathy, II) modulating the level of activity of a K-Ras protein in a cell, and III) K-Ras protein bound conjugates, does not reasonably provide enablement for using Formulas I-VI for i) treating any and all K-Ras associated diseases, N-Ras associated diseases, H-Ras associated diseases, ii) modulating the level of activity in a N-Ras or H-Ras protein in a cell, or iii) H-Ras or N-Ras bound conjugates. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the nature of the invention,
2- the breadth of the claims,
3- the state of the prior art,
4- the predictability of the art,
5- the amount of direction or guidance provided
6- the presence or absence of working examples,
7- the quantity of experimentation necessary, and
8- the relative skill of those in the art.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Undue experimentation is required by one skilled in the art to determine enablement of the instant disclosure as claimed due to the following:
The nature of the invention (1) and the breadth of the claims (2)
The nature of the invention and breadth of claim(s) are compounds of Formulas I-VI (claims 1, 13, 43, 50, 76, 118, 119) for the treatment of cancer (claims 77, 120), the treatment of a K-Ras, N-Ras, H-Ras-associated diseases broadly (claims 79, 80, 81, 121-123), the modulation of activity of K-Ras, N-Ras, or H-Ras broadly (claims 82, 88, 94, 124-126), and conjugates of Formulas I-IV with K-Ras, N-Ras, or H-Ras proteins (claims 100, 106, 112, 127-129).
The instant gena of Formula I-IV are not structurally defined (claims 1, 43, 118), or partially structurally defined (claims 13, 50).
The specification defines “treatment” as:
any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline, making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.” (see instant spec. at p. 41 ¶[0136]).
The specification defines “associated-disease” as:
the disease…is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g. inhibiting or activating) the substance…(see instant spec. at p. 57 ¶[0189]).
The specification defines “subject” as:
a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals…other non-mammalian animals.
The broadest reasonable interpretation includes a patient population of anyone, since any human prone to a disease encompasses prophylactic subjects.
The state (3) and predictability (4) of the art
MPEP § 2164.05(a) states if a publication demonstrates that those of ordinary skill in the art would not find that a particular invention was not enabled years after the filing date, the publication would be evidence that the claimed invention was not possible at the time of filing.
Regarding K-Ras as a target for disease and unpredictability in structure-function relationships, McGregor et. al.1 states “[t]here is a growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors” (see McGregor at Abstract). McGregor goes on to say “[t]he resulting data reveal that relatively minor changes in the electrophilic warhead can result in dramatic changes in the ligand binding mode and labeling rate, highlighting the need to optimize the spatial relationship between an electrophile and its amino acid nucleophile” (see McGregor at Conclusions).
This tells artisans that structure determines function, and minor changes to structure effect major changes in function. Currently, Applicant is claiming a very specific function with no structure in claims 1, 118.
Kim et. al.2 teaches that just because a species modulates one Ras does not mean it will modulate another, “[t]he ability of the inhibitor to suppress nucleotide exchange by HRAS or NRAS was several orders of magnitude less than that for KRAS (Fig. 1d,e)” (see Kim at p. 162 left col. ¶2). Kim’s K-Ras cysteine residue targeting drugs are not capable of targeting other G12 residues, “[t]hese drugs, however, require a reactive cysteine residue for inhibition and cannot be used against non-G12C mutants, which constitute most KRAS alterations in cancer. As such, efforts to identify therapeutics that enable broad inhibition of KRAS mutants are continuing” (see Kim at p. 160 left col.). Yu et. al.3 teaches one inhibitor, “the first”, that covalently bind to either an aspartate residue in K-Ras(G12D) or a cysteine residue in K-Ras(G12C) (see Yu at Abstract). Yu teaches inhibitors of varying structure have varying success in modifying K-Ras(G12D) (see Yu at p. 20405 Figure 2).
This would lead an artisan to not accept a compound which may bind to the serine residue mutant will bind to the threonine residue mutant (instant claim 118), or one that binds to an aspartate residue mutant will bind to a glutamate residue mutant (instant claim 1) with a reasonable expectation of success.
Further, regarding claims 79-81, 121-123 a method of treating an “associated disease” includes diseases not yet discovered and not yet discovered to be responsive to inhibition of a Ras protein. It would certainly require undue experimentation to discover the enabled embodiments encompassed by claims 79-81, 121-123.
The prior art provides enablement for targeting specific residues of specific K-Ras mutants with specific species.
The amount of direction or guidance provided (5) and the presence or absence of working examples (6)
The specification provides the following embodiments:
Example 1 shows β-lactone moieties in five compounds for binding to mutant K-Ras serine residues (K-Ras(G12S)) (see instant spec. at pp. 319-324). All five compounds are structurally similar sharing a common core:
Compound 1’
Compound 2’
Compound 3’
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210
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164
210
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170
192
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Compound 4’
Compound 5’
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174
184
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Example 2 shows the synthesis of species 1’, 2’, 3’, 4’, 5’ and describes experimental methods without results (see instant spec. at pp. 328-357).
Example 3 shows the % modification of K-Ras vs mutant K-Ras (G12S) of 23 compounds (see instant spec. at pp. 357-358).
Example 4 shows β-lactone moieties in seven compounds (compounds 1-7, Figures 19A, 26A, 29A) for binding to mutant K-Ras aspartate (K-Ras (G12D)) residues (see instant spec. at pp. 358-363). Applicant notes the enantiomer of the 2R,3S compound 4 did not react with K-Ras(G12D) (see instant spec. at p. 360 ¶[1059]).
Example 5 shows the synthesis of compounds 1-7 and describes experimental methods without results (see instant spec. at pp. 363-383).
All seven compounds are structurally similar and share a common core:
Compound 1
Compound 2
Compound 3
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Compound 4
Compound 5
Compound 6
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Compound 7
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Example 6 shows the % modification of K-Ras vs mutant K-Ras (G12SD) of 36 compounds (see instant spec. at pp. 383-384). Notably, 14 species do not bind to a K-Ras at all, and 6 unselectively under 10%.
Applicant’s disclosure emphasizes unpredictability in the art of inhibiting binding to K-Ras proteins. Applicant does not show the disclosed compounds are capable of binding to H-Ras or N-Ras. Applicant does not show the compounds bind to anything other than K-Ras serine 12 residue or K-Ras glutamate 12 residue (i.e. does not appear to note glutamate or threonine, as functionally claims ins claims 1, 118).
The specification provides enablement for using the structurally defined disclosed compounds for I) treating a K-Ras(G12D)-associated or K-Ras(G12S)-associated disease selected from: cancer and RASopathy, II) modulating the level of activity of a K-Ras protein in a cell, and III) K-Ras protein bound conjugates.
Nowhere in the specification is it explained how such any disease encompassed by the claims are to be prevented through the administration of the claimed compounds.
Therefore, the full scope of the compounds as functionally claimed, the methods comprising, or the conjugates thereof are not enabled.
The quantity of experimentation necessary (7) and the relative skill of those in the art (8)
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. Because of the unknown predictability in the art (as discussed above) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not be able to make a compound of Formula I-VI, since they are only defined by what they do and not what they are. In other words, an artisan may ask “how do I know what to make?”. An artisan would not accept that compounds of Formula I-VI could be used as modulators or treatments or covalently-bound conjugates as claimed.
Brenner v. Manson states "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (Brenner v. Manson 383 U.S. 519, 536, 148 USPQ 689, 696 (1966), cited in Genentech Inc. vs. Nova Nordisk 42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, little experimentation provided is drawn to treatment of diseases encompassed by the claims. A review of the state of the art fails to reveal that K-Ras mutant inhibitors are useful as therapeutic treatment as claimed (e.g. any and all cancer). Determining if compounds of Formula I-VI would be therapeutic for any particular disease state would require careful analysis and replicability of a composition comprising a compound of Formula I-VI, formulation into a suitable dosage form, assay testing to correlate clinical efficacy, identifying off-targets, subjecting to animal trials, and subjecting to clinical trials.
All this is undue experimentation given the limited guidance and direction provided by Applicants.
Conclusion
Applicant is merely expressing a wish already known in an unpredictable art - to target amino acids in the switch II binding pocket of mutant K-Ras with covalent inhibitors (as taught by McGregor). While targeting cysteine, arginine, and aspartate residues in switch II pocket are already known, the claims are attempting to claim yet-to-be discovered inhibitors without any (or very little) associated structure. The instant specification only discusses the use of beta-lactones and beta-lactam moieties in structurally similar species for targeting specifically K-Ras(G12S) and K-Ras(G12D).
Accordingly, the inventions of claims 1, 13, 43, 76-77, 79-82, 88, 94, 100, 106, 112, 118-129 do not comply with the enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Suggested Amendment
The Examiner suggests amending as follows:
Cancel claims 80, 81, 88, 94, 106, 112, 122, 123, 125, 126, 128, 129.
Amend claims 1 and 118 as discussed above in the 112a Written Description rejection.
Amend claims 79 to include the limitation: wherein the K-Ras(G12D)-associated disease is selected from: cancer and RASopathy.
Amend claim 121 to include the limitation: wherein the K-Ras(G12S)-associated disease is selected from: cancer and RASopathy.
Conclusion
Claims 1, 13, 43, 76-77, 79-82, 88, 94, 100, 106, 112, 118-129 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SOPHIA J REILLY whose telephone number is (703)756-5669. The examiner can normally be reached 9:00 am - 5:00 pm EST M-F.
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/S.R./Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
1 Cite No. 47 in the IDS filed 11/15/24. McGregor et. al. "Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes" Biochemistry 2017, 56, 25, 3178-3183. DOI: 10.1021/acs.biochem.7b00271. Hereinafter McGregor.
2 Kim et. al. "Pan-KRAS inhibitor disables oncogenic signalling and tumour growth" Nature 2023, 619, 160-166. DOI: 10.1038/s41586-023-06123-3. Hereinafter Kim.
3 Cite No. 60 in the IDS filed 11/15/24. Yu et. al. "Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles" J. Am. Chem. Soc. 2023, 145, 37, 20403–20411. DOI: 10.1021/jacs.3c05899. Hereinafter Yu.
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