DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 22, 23, and 25-29 are pending.
Priority
This application is filed 07/10/2024, and claims the benefit of domestic priority as below:
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Information Disclosure Statements
No IDS(s) received.
Abstract
The abstract of the disclosure is objected to because the abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. Currently, the abstract has 31 words.
The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The current submitted abstract is the front pages of PCT application. Examiner requests to bring in narrative form to satisfy the abstract requirement.
Correction is required. See MPEP § 608.01(b).
Claim interpretation
Claims are interpreted in accordance with the broadest reasonable interpretation (BRI) standard
consistent with the specification (See MPEP 2111).
With respect to claim 25, the term “cancer” is not limited by tumor type, mutation status, renin-angiotensin system (Ras) dependency, or the presence of any Ras mutation. Accordingly, claim 25 is interpreted to encompass cancer generally, including both mutation positive and mutation negative cancers.
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 28 and 29 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.
The term “a Ras protein-related disorder” in claim 28 is a relative term which renders the claim indefinite. The term “a Ras protein-related disorder” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “Ras protein related disorder” does not clearly define the metes and bounds of the claimed method. It is unclear whether the disorder must be caused by a Ras mutation, characterized by aberrant Ras activity, associated with Ras expression or signaling, treatable by Ras inhibition, or merely biologically related to a Ras proteins.
The phrase “contacting the cell with an effective amount of a compound” in claim 29 is a relative term which renders the claim indefinite. The phrase “contacting the cell with an effective amount of a compound” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, the phrase “effective amount” is not defined by the claim , and claim 29 does not provide an objective boundary for determining what amount of the compound is “effective”. Moreover, Ras is an intracellular target, but claim 29 merely recites "contacting the cell" with a compound without specifying conditions sufficient for the compound to enter the cell, reach intracellular Ras, and produce the alleged Ras-inhibitory effect. Claim 29 is not limited to a particular cell type, Ras isoform, assay condition, exposure time, concentration range, intracellular concentration, cellular uptake condition, or threshold degree of Ras inhibition.
Claim Rejections - 35 USC § 112, 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 25-29 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while providing disclosure that the compounds are RAS inhibitors and are useful in the treatment of certain RAS associated cancer or RAS protein related disorders, does not enable the full scope of the claimed methods. 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 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
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 the 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).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by 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 quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
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). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, and state and predictability of the art
The instant claims relate to methods of treating cancer and Ras protein related disorders using compounds of claim 22, or a pharmaceutically acceptable salt thereof. The claims involves Ras directed therapy and cellular Ras inhibition, which are highly mutation dependent, isoform dependent, cell context dependent, and disease context dependent. The relevant art is highly unpredictable at the time of filing because Ras biology and Ras directed therapy are recognized as complex, mutation dependent, isoform dependent, cell context dependent, and disease context dependent.
Hobbs et al. (RAS isoforms and mutations in cancer at a glance, J. Cell Sci., 129 (7), 1287–1292, pub’d 04/01/2016) teaches that Ras proteins function as GDP/GTP regulated binary switches that control diverse signaling networks and that gain-of-function Ras mutations occur in a substantial fraction of human cancers (abstract). Hobbs further teaches that, despite more than three decades of effort, no anti-Ras therapies had reached clinical application, and that this failure reflected an underestimation of Ras complexity (conclusion). Hobbs also teaches that the four human Ras proteins are not functionally identical and that different Ras mutations can have mutation specific consequences on Ras structures, biochemistry, and biology (abstract and introduction).
Moreover, Mo et al. (RAS variant signalling, Biochem. Soc. Trans., 46(5), 1325-1332, pub’d 10/03/2018) reports that Ras isoforms and different activating mutations differentially contribute to normal and disease associated biology, including cancer and Rasopathies (abstract and Ras isoform contributions to disease section), and Canon et al. (The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumor immunity, Nature, 575(7781), 217-223, pub’d 10/30/2019) reports that AMG510 as a KRAS G12C inhibitor (i.e., a mutation specific inhibitor), not a general Ras inhibitor applicable to all Ras mutations, all cancers, or all Ras protein related disorders (Mutant-selective tumor inhibition in vivo section). These teachings show that therapeutic activity or cellular Ras inhibition could not be predictably extrapolated from selected Ras inhibition data or selected cancer cell activity to cancer generally, Ras mutated cancers generally, Ras protein related disorders generally, or Ras protein inhibition in cells generally.
Lastly, Hong et al. (KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors, N. Engl. J. Med., 383, 1207-1217, pub’d 09/20/2020) teaches that sotorasib is tested in patients whose tumors harbored KRAS p.G12C, yet tumor type responses differed materially. Hong states that the KRAS p.G12C mutation occurs in 13% of non–small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers (abstract), and the clinical activity is described in the context of KRAS p.G12C mutant advanced solid tumors rather than mutation unselected cancers (discussion section), and Ring et al. (Endometrial cancers with activating KRas mutations have activated estrogen signaling and paradoxical response to MEK inhibition, Int. J. Gynecol. Cancer, 27(5), 854–862, pub’d 06/01/2018) teaches MEK inhibition in KRAS mutant endometrial cancer cells causes activation of estrogen receptor signaling and prevents suppression of ERK1/2 and p90RSK signaling (i.e., a paradoxical response to pathway inhibition).
These references support the proposition that even allele selected RAS inhibition could not be extrapolated broadly to unselected pancreatic cancer, colorectal cancer, NSCLC or endometrial cancer, and that inhibition of the RAS/MAPK pathway may have context dependent and counterproductive signaling effects in endometrial cancer, rather than predictable therapeutic efficacy. The references also support that Ras inhibition cannot be predictably generalized across all Ras proteins, cell types, mutation states, and cellular contexts encompassed by claim 29.
Although the specification provides certain narrower embodiments directed to Ras mutant cancers, cancers characterized by aberrant Ras activity, selected cancer/Ras mutation combinations, or selected Ras assays, it does not provide a scientific or clinical framework sufficient to support treatment or Ras protein inhibition across the full scope of claims 25-29. Accordingly, in view of the mutant dependent, isoform dependent, cell context dependent, and disease-context-dependent nature of Ras biology, and Ras-directed therapy with teachings from Hobbs, Mo, Canon, Hoang and Ring, a person of ordinary skill in the art would not have reasonably expected that activity shown for selected compounds or selected Ras-associated cancer models would predict therapeutic efficacy or Ras protein inhibition for the full set of specifically recited compounds of claim 22 across the full scope of cancer, the four recited cancers irrespective of mutation status, Ras-mutated cancer, and Ras protein-related disorder, and cellular Ras inhibition encompassed by claims 25-29. Thus, the nature of the invention and the state of the art weight against enablement because the specification does not provide a scientific or clinical framework sufficient to support the broad therapeutic and cellular inhibition methods recited in claims 25-29, and using the claimed methods commensurate with their full scope would require undue experimentation.
The breadth of the claims
The claims are broad insofar as they recite methods of treating “cancer”, four different cancer types, “cancers comprising a Ras mutation” generally, “Ras protein related disorder” generally, and inhibiting a Ras protein in a cell generally.
Claim 25 broadly encompasses treating cancer without limitation to particular cancers, Ras dependent cancers, cancers characterized by aberrant Ras activity, cancers comprising a Ras mutation, or any particular cancer subtype. Claim 26 depends directly from claim 25 and limits the cancer recited in claim 25 to four specific cancers, including pancreatic cancer, colorectal cancer, non-small cell lung cancer, and endometrial cancer. However, claim 26 does not require that those cancers comprise a Ras mutation or otherwise be Ras dependent. Claim 27 depends directly from claim 25 and limits the cancer recited in claim 25 to one that comprises a Ras mutation. However, claim 27 still broadly encompasses Ras mutated cancers generally, without limitation to particular Ras isoforms, particular Ras mutations, Ras dependent tumor contexts, cancer characterized by aberrant Ras activity, or specific cancer subtypes. Claim 28 independently encompasses treating a Ras protein related disorder without limitation to cancer, Ras mutant cancer, Ras dependent cancer, a disorder characterized by aberrant Ras activity, or any specific Ras associated disease state. Claim 29 independently encompasses inhibiting a Ras protein in a cell by contacting the cell with an effective amount of a compound of claim 22, without limitation to any particular cell type, Ras isoform, Ras mutation, cellular context, assay condition, concentration range, exposure time, or threshold degree of Ras inhibition.
"Cancer" as a proliferative disease is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, as seen, for example, in cancers of the breast, brain and salivary glands. They can occur in nearly much every part of the body through different molecular mechanisms. The prior art recognized that there has never been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." (<https://www.uspto.gov/patents/laws/patent-examination-policy-mpep-staff-35-usc-112-1st-para-enablement#7f> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers, but the art has not established a compound effective against cancer generally , or even a majority of cancer.
The current specification may support prediction within narrower Ras associated contexts. For example, the specification describes diseases or disorders characterized by aberrant Ras activity due to a Ras mutant, identifies cancer as an embodiment, and identifies selected cancers and selected Ras mutations. However, the full scope of claims 25-29 is not limited to those narrower contexts. For example, the specification describes disease or disorders characterized by aberrant Ras activity due to a Ras mutant, identifies cancer as an embodiment, and identifies selected cancers and selected Ras mutations. However, the full scope of claims 25-29 is not limited to those narrower contexts.
Accordingly, in view of the mutant-dependent, isoform-dependent, cell context dependent, and disease-context-dependent nature of Ras biology, and Ras-directed therapy with teachings of Hobbs, Mo, Canon, Hong and Ring, the breadth of the present claims exceeds the scope of the specification’s working examples and predictive guidance.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides disclosure that would allow a person of ordinary skill in the art to predict activity within narrower Ras associated or Ras mutant contexts. For example, the specification states that the compounds are Ras inhibitors and are useful in the treatment of cancer (lines 4-5, page 333). The specification further discloses methods of treating a disease or disorder characterized by aberrant Ras activity due to a Ras mutant, and states that, in some embodiments, the disease or disorder is cancer (lines 25-27, page 339). The specification also identifies particular cancer types and Ras mutations, including pancreatic cancer, colorectal cancer, non-small cell lung cancer, and endometrial cancer, and provides in vitro assays for evaluating activity in selected K-Ras mutant cancer cell lines (line 23 in page 325 – line 13, page 326).
However, the disclosure does not provide therapeutic guidance addressing the full scope of cancers, cancers comprising a Ras mutation, and Ras protein related disorders encompassed by claims 25-28. Nor does the disclosure provide guidance commensurate with the full scope of claim 29, which broadly encompasses inhibiting a Ras protein in a cell without limitation to a particular cell type, Ras isoform, mutation, assay condition, exposure time, concentration range, or threshold degree of inhibition. Nor does the disclosure establish that one of ordinary skill in the art could extrapolate from the disclosed working examples to the full therapeutic or cellular inhibition scope of the claims without undue experimentation. The disclosure also does not provide sufficient clinical or other representative treatment data, in vivo treatment data across representative disease classes, dosing regimens correlated to particular disease states, pharmacodynamic data, therapeutic window analyses, disease specific guidance, or representative cellular inhibition data across Ras isoforms, mutation states, and cell types adequate to extrapolate from selected Ras related assays to the full scope of the claimed methods.
The lack of specific contexts or limitations worsens the lack of direction and the absence of working examples. Claim 25 extends to cancer generally. Claim 26, although directly dependent from claim 25 and limited to cancer types, still extends to the four recited cancers irrespective of mutation status, including both mutant and wild type cancers. Claim 27, although directly dependent from claim 25 and limited to cancers comprising a Ras mutation, still extends to Ras mutated cancers generally without limitation to particular Ras isoforms, particular Ras mutations, Ras dependent tumor contexts, or specific cancer subtypes for which the specification provides working examples or sufficient guidance. Claim 28 extends further to Ras protein related disorders generally, without limiting the disorder to cancer, Ras mutant disease, or a disease characterized by aberrant Ras activity. Claim 29 extends to Ras protein inhibition in a cell generally, without limiting the claim to the specific Ras proteins, mutations, cell types, compounds, concentrations, exposure times, or assay conditions for which the specification provides working examples or predictive guidance.
Accordingly, the specification lacks sufficient therapeutic and cellular inhibition direction and representative working examples commensurate with the full scope of the claimed methods.
The quantity of experimentation necessary
Given the limited predictability of Ras biology and Ras directed therapy, the breadth of claims 25-29, and the absence of sufficient guidance or representative working examples commensurate with the full scope of those claims, a person having ordinary skill in the art would be required to engage in extensive experimentations to engage in substantial experimentation to practice the claimed methods across their full scope. Such experimentation would include determining whether the specifically recited compounds of claim 22 are therapeutically effective in cancer generally, the four recited cancers irrespective of mutation status, cancers comprising Ras mutations generally, and Ras protein related disorders generally, including disease contexts not limited to particular Ras isoforms, particular Ras mutations, Ras dependent tumor contexts, cancer characterized by aberrant Ras activity, or specific cancer subtypes. For claim 29, such experimentation would also include determining which compounds of claim 22 inhibit which Ras proteins, in which cells, under which assay conditions, at what concentrations and exposure times, and to what degree.
Hobbs, Mo, Canon, Hong and Ring discussed above, show that Ras biology is mutation dependent, isoform dependent, cell context dependent, and disease context dependent. In view of that unpredictability, therapeutic efficacy or cellular Ras inhibition could not be predictably extrapolated from selected Ras inhibition data or selected Ras associated cancer models to the full scope of the claimed methods. Therefore, practicing the full scope of claims 25-29 would require substantial additional screening and validation to determine which compounds of claim 22 are effective, in which cancer or mutant contexts, under what treatment conditions across the claimed therapeutic indications, and which compounds inhibit which Ras proteins in which cellular contexts under which conditions.
Accordingly, the instant claims 25-29 do not comply with the enablement requirement of §112, because practicing the claimed invention would require undue experimentation by a person of ordinary skill in the art without reasonable assurance of success.
Conclusion
Claims 22-23 are allowed.
Claims 25-29 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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