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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in
37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 23, 2025 has been entered.
Response to Amendment
Claim listing filed on September 23, 2025 is pending. Claims 1-53, 58-59, 63, and 67 are cancelled. Claims 54, 64, and 73 are amended. Claims 54-57, 60-62, 64-66, and 68-73 are examined upon their merits.
Withdrawn Claim Rejections
Applicant’s cancellation of Claims 58-59 has rendered all previous rejections directed to these claims moot.
The rejection of Claims 54-57, 60-62, 64-66, and 68-73 under 35 U.S.C. 112(b) as being indefinite for reciting “retains GTPase activity” is withdrawn in view of Applicant’s amendments. The claims now recite a KRAS mutant that “has GTPase activity.” The broadest reasonable interpretation of the claim language is that that a KRAS mutant with any level of GTPase activity is encompassed by “has GTPase activity.” Hunter et al. Mol Cancer Research 2015 (of record) teaches that G12C, G12D, G12V, and G13D have GTPase activity based on their GTP hydrolysis rates (49, 19, 4.2, and 9.6 x10-5/s respectively) (Figure 2 and Table 1). These mutations are non-limiting examples of what are understood in the art as “KRAS mutant that has GTPase activity.”
The rejection of Claims 71-72 under 35 U.S.C. 112(b) as being indefinite for defining the agent with functional language is withdrawn upon further consideration. Claim 71 defines wherein the agent is a soluble CNTFR polypeptide which provides an appropriate structure for the function of binding CLCF1 and inhibiting interaction between CLCF1 and CNTFR.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 54-57, 60-62, 64-66, 68-70, and 73 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 is maintained.
Applicant's arguments filed September 23, 2025 have been fully considered but they are not persuasive. Applicant argues that the amended claims recite “wherein the agent is a protein-based agent” which provides a structure for the claimed agent. The specification does not clearly define the metes and bounds of “protein-based agent” and only lists non-limiting examples by reciting “protein-based agents (e.g., peptides, antibodies, engineered ligands, engineered receptors, etc.)” (page 11, lines 30-31). It is unclear if “protein-based agents” are required to be proteins comprising naturally-occurring amino acids or if “protein-based agents” can broadly include ribozymes that are RNA molecules that act like protein enzymes or synthetic proteins that comprise non-natural amino acids. The structural metes and bounds of “protein-based agents” are unclear and the rejection is maintained.
Claim Rejections - 35 USC § 112 (New)
Claim 72 is 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 72 recites “mutations that reduce the binding affinity of the soluble CNTFR polypeptide for gp130, LIFR, or both” and “mutations that increase the binding affinity of the soluble CNTFR polypeptide for CLCF1.” These phrases are considered functional language because the features (the mutations) are defined by what they do (reduce or increase binding affinity) rather than by what they are (MPEP § 2173.05(g)). To determine if functional language is ambiguous, the following factors are considered: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. These factors are examples of points to be considered when determining whether language is ambiguous and are not intended to be all inclusive or limiting (MPEP § 2173.05(g)). Claim 72 recites a result obtained (reduced or increased binding affinity) without any required structure for the mutations. As such, the metes about bounds of the mutations cannot be readily determined from the claim language, and Claim 72 is rejected as being indefinite.
Claim 72 recites “reduce the binding affinity…relative to a CNTFR polypeptide having an amino acid sequence comprising SEQ ID NO: 8” and “increase the binding affinity…relative to a CNTFR polypeptide having an amino acid sequence comprising SEQ ID NO: 8.” While these phrases are considered functional language (see above rejection), they also include relative terminology, specifically the terms “reduce” and “increase” (MPEP § 2173.05(b)). What is the numerical threshold of reduce and increase? For example, are non-statistically significant changes encompassed by these relative terms? Further, the reduction and increase in binding affinity are compared to the binding affinities of wild-type CNTFR (SEQ ID NO: 8), but these values are not clearly defined in the specification or in the art prior to filing. The specification does not define the binding affinity (KD) of wild-type CNTFR to gp130 or LIFR. Further, the specification teaches that the binding affinity of wild-type CNTFR to CLCF1 is too low to be measured (Fig. 2d). If the binding affinity of wild-type CNTFR to CLCF1 cannot be measured, it is unclear what is encompassed by an increase relative to this unknown value. The relative binding affinities are not described in the specification such that one of ordinary skill in the art would understand what is claimed, and Claim 72 is rejected for indefinite relative terminology.
Claims 54, 60-62, 64-66, and 68-72 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 treating KRAS mutant lung cancer (Claims 55-57), does not reasonably provide enablement for treating all types of KRAS mutant cancer (Claim 54). 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.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is
“undue”. 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, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex, encompassing the treatment of any KRAS mutant cancer (Claim 54) which encompasses KRAS mutant pancreatic ductal adenocarcinoma (PDAC). When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. Sarantis et al., World J Gastrointest Oncol. 2020 (of record) teaches that PDAC is one of the most lethal diseases with an average 5-year survival rates of less than 10% (abstract). Additionally, Sarantis teaches that available treatments such as chemotherapy, surgery, and radiation have been widely used, but they have not exhibited any significant improvements in clinical outcomes (introduction). Treatments that work well in other cancer types, such as immunotherapies, do not show promise in pancreatic cancer (introduction). Similarly, Jaber, N. National Cancer Institute 2021 (of record) teaches that the anti-cancer drug sotorasib is effective in treating KRAS mutant lung cancer but less effective in treating KRAS mutant pancreatic cancer due to differences in KRAS mutation signatures (paragraph 9). The art shows a continued lack of predictability even after the effective filing date of the instant invention, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in treating any type of KRAS mutant cancer, specifically PDAC.
Level of skill in the art:
The level of skill would be high encompassing oncology, genetics, protein science, gene therapy, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification offers no examples of treating a KRAS mutant cancer other than lung cancer. Example 4 demonstrates that KRAS mutant lung adenocarcinoma cell lines are more sensitive to treatment than wild-type KRAS lung adenocarcinoma cell lines (pg 35, lines 1-4). However, this correlation in lung adenocarcinoma cells offers no specific guidance on the treatment of other KRAS mutant cancers where mutational signatures differ.
A person having ordinary skill in the art would have to make a substantial inventive contribution in order to treat any type of KRAS mutant cancer such as PDAC, since there is no guidance within the disclosure as filed pertaining to this embodiment.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to practice the presently claimed invention would be unable to do so without engaging in an unknown quantity of experimentation. Given that the nature of the claims is in vivo treatment, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models, that are predictive of treatment in a representative number of KRAS mutant cancer types in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the treatment with a reasonable expectation of success.
The instant specification does not enable the invention to treat any type of KRAS mutant cancer (Claim 54).
Claim Rejections - 35 USC § 103 (Maintained)
The rejection of Claims 54-57, 60-61, 66, and 68-73 under 35 U.S.C. 103 as being unpatentable over Vicent et al., Cancer Res. 2012 (of record) in view of Kim et al. WO 2018/128745 (of record) and Kim et al. WO 2018/106790 (of record) is maintained. Kim et al. WO 2018/128745 will be referred to as “Kim 1”, and Kim et al. WO 2018/106790 will be referred to as “Kim 2”.
Applicant's arguments filed September 23, 2025 have been fully considered but they are not persuasive. Applicant argues that the connection between sensitivity of KRAS mutant cancer to treatment with the agent recited in claim 54 is neither taught not contemplated in any of the cited references, and the Office has used impermissible hindsight reasoning to find references that describe the cancer cells used in Vicent as KRAS mutant cancer having GTPase activity. As of record in the final rejection filed 04/23/2025, Vicent teaches that KRAS mutant G12D tumor cells carrying shRNAs directed against cntfr were significantly smaller than controls, and Vicent concludes that loss of CLCF1-CNTFR signaling causes a consistent decrease in KRAS mutant tumor formation. Examiner relies on the teachings of Kim 1 and Kim 2 to specifically teach the agents that inhibit CLCF1-CNTFR signaling as described in Claim 54. One of ordinary skill would understand that both the shRNAs from Vicent and the agents taught by Kim 1 and Kim 2 mechanistically inhibit CLCF1-CNTFR signaling. Thus, the Examiner maintains that the connection between sensitivity of KRAS mutant cancer to treatment with agents that inhibit CLCF1-CNTFR signaling is taught by the cited references. In response to the alleged hindsight reasoning, the teachings of Johnson and Hunter were relied upon to teach the inherent characteristics of the LKR10 cells taught by Vicent. Vicent teaches that a KRAS-driven lung adenocarcinoma model was used in the study (introduction paragraph 3), but does not specifically define the characteristics of the LKR10 cells. As of record in the final rejection filed 04/23/2025, Johnson defines that the LKR10 cells are a model of KRAS G12D mutant lung carcinoma, and Hunter teaches that the KRAS G12D mutation has GTPase activity. MPEP § 2131.01 states that an extra reference or evidence can be used to show an inherent characteristic of the thing taught by the primary reference. Further, MPEP § 2112.II-III states that a prior art rejection is appropriate when the prior art product seems to be identical except that the prior art is silent as to an inherent characteristic, and the fact that a characteristic is a necessary feature or result of a prior art embodiment is enough for inherent anticipation even if that fact was unknown at the time of the prior invention. Vicent teaches treating LKR10 tumor cells by disrupting CLCF1-CNTFR signaling. Because the LKR10 tumor cells inherently possess the KRAS K12D mutation which inherently has GTPase activity, the cited art reads on the instant claims without impermissible hindsight reasoning.
Applicant argues that Vicent provides no teaching or suggestion that the LKR10 cells are sensitive to shRNAs directed against cntfr because they have a mutant KRAS with GTPase activity. Examiner maintains that it is unnecessary for the art to teach the mechanistic rationale behind why a treatment is effective. It is sufficient that Vicent teaches that inhibiting CLCF1-CNTFR signaling successfully decreases KRAS mutant tumor formation. One of ordinary skill would understand from the cited art that administering an agent that inhibits CLCF1-CNTFR signaling can treat an individual with KRAS mutant lung cancer with a reasonable expectation of success. Applicant’s arguments are not persuasive and the rejection is maintained.
The rejection Claims 54-57, 60-62, 64-66, 68-73 under 35 U.S.C. 103 as being unpatentable over Vicent et al., Cancer Res. 2012 (of record) in view of Kim et al. WO 2018/128745 (of record) and Kim et al. WO 2018/106790 (of record) as applied to Claims 54-57, 60-61, 66, 68-73 above, and further in view of Blumenschein, et al. Ann Oncol. 2015 (of record) and Guan, et al. Ann Surg Oncol. 2013 (of record) is maintained.
Applicant's arguments filed September 23, 2025 have been fully considered but they are not persuasive. Applicant argues that a person of ordinary skill in the art would not arrive at the claimed invention which requires treating an individual identified as having a KRAS mutant cancer characterized by a KRAS mutant that has GTPase activity as supported by the instant inventors’ novel discoveries. It is of record that Vicent teaches treating KRAS K12D mutant lung adenocarcinoma. It is also of record that Blumenschein teaches identifying patients eligible for treatment based on their KRAS mutational status. Specifically, Blumenschein teaches that KRAS mutations are detected in 25% of lung adenocarcinomas but with limited therapeutic progress in this population as no targeted therapies were approved for KRAS-mutant NSCLC at the time of Blumenschein’s publication in 2015 (introduction paragraph 1). Therefore, therapies that show preclinical activity in KRAS-mutant NSCLC lines are tested in clinical trials that specifically identify and recruit patients with KRAS mutational status (introduction paragraph 2) to try to provide better therapeutic options for this patient population. Because Vicent teaches preclinical evidence that inhibiting CLCF1-CNTFR signaling can successfully treat KRAS G12D mutant lung cancer, it is obvious in view of Blumenschein to identify patients with KRAS mutant lung cancer and administer agents that inhibit CLCF1-CNTFR signaling as this approach to personalized medicine in this patient population is already established. Further, Kim 1 and Kim 2 teach that expression of CNTFR was observed in KRAS G12D tumor models and their results indicate that the CLCF1-CNTFR signaling axis is active in lung adenocarcinoma and that it may have a role in oncogenesis, particularly in tumors driven by oncogenic KRAS (Kim 1 Example 3 and Kim 2 Example 15) which further supports identifying patients with KRAS mutant lung cancer and administering an agent that inhibits CLCF1-CNTFR signaling. Note, new sections of Blumenschein, Kim 1, and Kim 2 are cited solely in response to Applicant’s arguments and not as new grounds of rejection. Therefore, identifying patients based on KRAS mutant cancer status and administering an agent that inhibits CLCF1-CNTFR signaling is obvious over the cited art. Applicant’s arguments are not persuasive, and the rejection is maintained.
Double Patenting (Maintained)
1. The rejection of Claims 54-57, 60-61, and 68 on the ground of nonstatutory obvious-type double patenting as being unpatentable over Claims 1, 11-12, and 15-17 of U.S. Patent No. 11,179,441 in view of Vicent et al., Cancer Res. 2012 (of record) is maintained.
2. The rejection of Claims 54-57, 60-61, and 70-72 are rejected on the ground of nonstatutory obvious-type double patenting as being unpatentable over Claims 1 and 12-17 of U.S. Patent No. 11,208,462 in view of Vicent et al., Cancer Res. 2012 (of record) is maintained.
3. The rejection of Claims 54-57, 60-61, and 68 are provisionally rejected on the ground of nonstatutory obvious-type double patenting as being unpatentable over Claims 54-61 and 65-68 of copending U.S. App. No. 17/531,439 in view of Vicent et al., Cancer Res. 2012 (of record) is maintained.
4. The rejection of Claims 54-57, 60-61, and 70-72 are provisionally rejected on the ground of nonstatutory obvious-type double patenting as being unpatentable over Claims 90-101 of copending U.S. App. No. 17/556,522 in view of Vicent et al., Cancer Res. 2012 (of record) is maintained.
Applicant's arguments filed September 23, 2025 have been fully considered but they are not persuasive. Applicant argues that the instant claims are patentably distinct from the patented claims and copending claims for the reasons established in the response to the rejections under § 103. Applicant argues that none of the patented or copending claims are directed to treating cancer in which a human patient is selected for treatment on the basis of their KRAS mutant status. As addressed in the 103 rejection above, Examiner maintains that Vicent teaches that KRAS mutant G12D tumor cells carrying shRNAs directed against cntfr were significantly smaller than controls, and Vicent concludes that loss of CLCF1-CNTFR signaling causes a consistent decrease in KRAS mutant tumor formation. One of ordinary skill would understand that the shRNAs from Vicent and the agents taught by the patented and copending claims all mechanistically inhibit CLCF1-CNTFR signaling. Thus, it would be obvious to one of ordinary skill that the agents described in the patented and copending claims can be administered to individuals to treat KRAS mutant cancer with a reasonable expectation of success. Applicant’s arguments are not persuasive, and the rejections are maintained.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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