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 .
Status of the Claims
Per Applicant’s amendment to the claims, submitted on 11/14/2025, claims 1, 6, 8, 27, 29, and 45-46 are amended, and claims 2-5, 7, 9-26, 28, and 30-44 are canceled. Currently, claims 1, 6, 8, 27, 29, and 45-46 are pending in the instant application.
Specification Objections – Withdrawn
Objections to Specification:
In light of Applicant’s amendment to the specification, the objections are hereby withdrawn. The indicated typographical errors have been corrected.
Claim Objections – Withdrawn
Objections to claims 27-29 and 45-46:
In light of Applicant’s amendment to the claims, the objections are hereby withdrawn. Claim 28 has been canceled, and claims 27, 29, and 45-46 have been amended to depend upon claim 1.
Claim Interpretation – Withdrawn
Interpretation of claims 43-44:
In light of Applicant’s amendment to the claims, claim interpretation is no longer required. Claims 43-44 have been canceled.
Claim Rejections - 35 USC § 112 Second Paragraph – Withdrawn
Rejection of claim 2:
In light of Applicant’s amendment to the claims, the rejection is hereby withdrawn. Claim 2 has been canceled.
Claim Rejections - 35 USC § 102 – Withdrawn
Rejections of claims 1-2 and 42:
In light of Applicant’s amendment to the claims, the rejections are hereby withdrawn. Claims 2 and 42 have been canceled. Claim 1 has been amended such that the Bendell prior art no longer anticipates the method of the claim. While Applicant has overcome the anticipation rejection by amending claim 1, rejection under 35 USC 103 is still necessitated and will be detailed herein.
Claim Rejections - 35 USC § 103 – Withdrawn
Rejections of claims 3-4, 5-8, 11-14, 30-34, 37-41, and 43-44:
In light of Applicant’s amendment to the claims, the rejections are hereby withdrawn. Claims 3-4, 5, 7, 11-14, 30-34, 37-41, and 43-44 have been canceled. Applicant has overcome the 102 rejection of claim 1 which was the basis for the indicated 103 rejections of the remaining claims 6 and 8. However, rejections under 35 USC 103 will be maintained over Bendell in view of Nawrocka (see maintained rejections below).
Claim Rejections - 35 USC § 103 – Maintained
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 6, 8, 27, 29, and 45-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bendell (previously referenced) in view of Nawrocka (previously referenced).
Response to Applicant Remarks:
In response to the previous Office Action, Applicant has amended claim 1 such that it now recites the content of canceled claims 5, 7, and 28, and has further amended claims 6, 8, 27, 29, and 45-46 to depend upon independent claim 1. However, apart from the aforementioned amendments, no substantive argument has been provided to traverse the rejections over Bendel in view of Nawrocka.
As reiterated by the Supreme Court in KSR, the framework for the objective analysis for determining obviousness under 35 U.S.C. 103 is stated in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Obviousness is a question of law based on underlying factual inquiries. The factual inquiries enunciated by the Court are as follows:
Determining the scope and content of the prior art;
Ascertaining the differences between the claimed invention and the prior art; and;
Resolving the level of ordinary skill in the pertinent art.
(A) In the case of the instant claims, the scope of claim 1 is now directed towards a method of treating cancer in a patient in need thereof, comprising administering taladegib, wherein the cancer is characterized in having an activated hedgehog pathway activated by a loss of function mutation in PTCH1, wherein the PTCH1 mutation is a frameshift mutation.
(B)The teachings of Bendell are drawn towards the administering of taladegib to patients suffering from basal cell carcinoma (BCC), wherein basal cell carcinoma is a cancer having an activated hedgehog pathway. The teachings of Bendell differ from the instant claims in that Bendell does not explicitly teach cancer wherein the hedgehog pathway is activated by a loss of function mutation in PTCH1. The teachings of Nawrocka ameliorate the deficiencies of Bendell because Nawrocka teaches that BCC is characterized by the highest mutation rate among cancers, with said mutations being predominantly loss of function PTCH1 mutations. Said mutations in PTCH1 are responsible for the loss of downstream ability to inhibit SMO, which in turn leads to upregulation of cell cycle effects.
(C) The aforementioned teachings of Bendell indicate the treatment of BCC using taladegib as an SMO inhibitor, while Nawrocka indicates that suffering from BCC having the recited PTCH1 mutation have impaired ability to inhibit SMO. A person of ordinary skill in the art would have found it prima facie obvious to combine the teachings of Bendell and Nawrocka to arrive at a method wherein taladegib is administered to patients suffering from BCC comprising an activated hedgehog pathway with the recited PTCH1 mutation, because there would be a reasonable expectation of success in treating such a condition.
Rejections:
Claim 1 recites a method of treating cancer in a patient, comprising administering taladegib, wherein the cancer is characterized in having an activated hedgehog pathway, wherein the hedgehog pathway is activated by a loss of function mutation in PTCH1; wherein the loss of function mutation in PTCH1 is a frameshift mutation resulting in a truncated protein.
Bendell teaches the treatment of basal cell carcinoma (BCC) in patients by administration of a compound of LY2940680 (taladegib), which is a SMO inhibitor (page 2082)1. The teachings of Bendell are drawn to phase I testing of taladegib and assessments of maximum tolerable dose (MTD). Bendell further indicates BCC as a cancer implicated by activation of hedgehog (Hh) signaling pathway (page 2082)2. Bendell does not explicitly teach cancer wherein the hedgehog pathway is activated by a loss of function mutation in PTCH1. However, the treatment of such cancers using taladegib would be obvious because Nawrocka teaches that such mutations are common in BCC and are responsible for activation of hedgehog pathway.
Nawrocka provides an overview on the pathology of BCC and mutations in PTCH1 implicated in hedgehog pathway disfunction. Nawrocka indicates that BCC is characterized by the highest mutation rate observed among cancers, such mutations predominantly being loss of function mutations in PTCH1 (page 2)3. PTCH1 gene encodes for the PTCH1 transmembrane protein; normally, PTCH1 regulates the hedgehog (HH) signaling pathway. A part of this regulatory function is the inhibition of SMO, and the subsequent downstream activation of GLI transcription factors, further activating cell cycle effects. Nawrocka further indicates BCC wherein PTCH1 loss of function mutations are due to frameshift (page 9)4.
Given that the teachings of Bendell are directed towards the use of taladegib for the treatment of BCC, and that Nawrocka teaches that loss of function mutations in PTCH1 are a cause of overactive SMO as a part of HH pathway regulation loss in BCC, it would have been prima facie obvious for a person of ordinary skill in the art to administer taladegib to a patient suffering from BCC wherein HH pathway is activated by a loss of function mutation in PTCH1, and wherein said PTCH1 mutation is a frameshift mutation because there would be a reasonable expectation of success in ameliorating such a condition.
Claim 6 further limits the method of claim 1 wherein the cancer is basal cell carcinoma.
As discussed in the claim 1 rejection, Bendell teaches the treatment of BCC using taladegib.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bendell and Nawrocka, in further view of Tothill (previously referenced).
Claim 8 further limits the method of claim 1 wherein the truncating frameshift mutation comprises S1203Afs*52.
As discussed above, Bendell teaches the treatment of BCC by administration of taladegib, while Nawrocka teaches the frameshift mutations in PTCH1 as a pathological driver BCC and associated HH pathway activation.
However, neither Bendell nor Nawrocka explicitly teach the mutations of the instant claim, and in particular, Applicant’s elected mutation S1203Afs*52. However, it would be obvious to treat cancer having such a mutation with a compound of Formula I because Tothill teaches that an S1203Afs*52 mutation in PTCH1 is a known therapeutic target of SMO inhibitors.
Tothill teaches genetic sequencing of cancers of unknown primary. Such sequencing being for the purpose of support in diagnoses of primary site of origin of said cancers, and possible treatment options. Tumor specimens were collected from 16 patients, sequenced, and genetic mutation hot spots identified. Of particular relevance is patient 2864, identified as having actionable lesions containing PTCH1 mutation S1203Afs*52, and further indicated as being a therapeutic target for SMO inhibitors (page 417, Table 2):
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Tothill further indicates that the mutation found in patient 2864 is a protein truncating PTCH1 deletion which implicates deregulation of HH signaling pathway, which may have conferred sensitivity to SMO inhibitors such as vismodegib (page 421)5. Taken together with the teachings of Bendell, it would have been obvious to use a taladegib to treat a cancer comprising an S1203Afs*52 mutation in PTCH1 because Bendell teaches taladegib as an SMO inhibitor, which is the same class of compounds indicated by Tothill.
In summary, Bendell teaches the treatment of BCC by administering the SMO inhibitor taladegib, Nawrocka teaches PTCH1 loss of function mutation as a driver of HH pathway activation, and Tothill teaches SMO inhibitors as a targeted therapeutic for PTCH1 mutation S1203Afs*52. Given the aforementioned teachings, a person of ordinary skill in the art would have found it prima facie obvious to treat a cancer having the mutation S1203Afs*52 in PTCH1 using taladegib because there would be a reasonable expectation that the administration of taladegib would have success in ameliorating cancers having the indicated mutation.
Claim(s) 27 and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bendell in view of Nawrocka.
Claim 27 further limits the method of claim 1 wherein taladegib is administered orally.
Bendell teaches the oral administration of taladegib (page 2082 Abstract)6.
Claim 29 further limits the method of claim 1 wherein the method comprises administering taladegib at a dosage of 50-200 mg of free base taladegib.
Bendell indicates study dosing range of 50-600 mg. However, MTD was determined to be 400 mg. Accordingly, Bendell indicates that various dosing of cohorts throughout the study were individually dosed at 50 mg, 100 mg, 200 mg, and 400 mg as shown in the figure below (page 2085, Fig 1):
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Bendell’s dosing of cohorts 1-3 at 50, 100, and 200 mg, respectively, obviates the dosing range of the instant claim.
Claim(s) 45-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bendell and Nawrocka, in further view of Gampala (Cells 2021, 10, 3135).
Claim 45 further limits the method of claim 1 wherein the method further comprises administering an additional anti-cancer agent.
As discussed in the rejection of claim 1, Bendell teaches a method of treating BCC by administering taladegib, while Nawrocka teaches PTCH1 frameshift mutations in BCC. Neither Bendell nor Nawrocka teach the combination dosing of taladegib with an additional anti-cancer agent. However, it would be obvious to combine taladegib and an additional anti-cancer agent because Gampala teaches combinations of SMO inhibitors and immune checkpoint inhibitors.
Gampala provides an overview of the state of the art regarding treatment SHH based cancers. Of particular relevance to the instant invention is Gampala’s suggestion of combination therapy utilizing HH inhibitors and immune checkpoint inhibitors (ICI). Gampala indicates that HH inhibitors suffer from various shortcomings, such as being ineffective in metastatic or recurrent cancers, or having diminished effectiveness in patients who develop adaptive resistance to the drugs (page 7)7. Gampala further indicates that a clinical trial testing combination therapy of vismodegib (an SMO inhibitor) and an anti-PD-1 antibody was able to synergistically reduce liver tumors in mice (page 8)8. Overall, Gampala teaches the potential for the combination of HH pathway drugs and ICI drugs to treat cancer, as provided in the figure below (page 8, Fig. 2):
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Given the teachings of each of Bendell, Nawrocka, and Gampala, it would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to be able to develop a combination therapy by administering taladegib and an additional anti-cancer agent such as an ICI, because there would be a reasonable expectation of synergistic anti-cancer activity.
Claim 46 further limits the method of claim 1 wherein the method further comprises selecting the patient based on elevated expression of PD-1.
As discussed in the rejection of claim 45, Gampala teaches the combination of SMO inhibitors and ICI drugs. Among the drugs listed are various SMO inhibitors as well as ICIs which target PD-L1 (page 4, Table 1):
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Given that the teachings of Gampala are directed towards the potential combinations of the above classes of drugs, it would be obvious to select a patient having elevated PD-L1 expression in the case where an SMO inhibitor such as taladegib were to administered in combination with a PD-L1 targeting ICI such as atezolizumab, avelumab, or durvalumab.
Conclusion
Claims 1, 6, 8, 27, 29, and 45-46 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3þ3 design, the dose was confirmed, and then treatment-naive and previously hedgehog (Hh)-inhibitor–treated patients with basal cell carcinoma (BCC) were enrolled.”
2 “This pathway is responsible for regulating normal physiologic processes, whereas aberrant activation of Hh signaling pathway is implicated in a number of human cancers, including basal cell carcinoma (BCC), medulloblastoma, and others (1, 2, 4).”
3 “BCC is characterized by the highest mutation rate observed among cancers, having over 65 mutations/Mbp (14, 15). The most frequent genetic alterations occurring in BCC are mutations disturbing the hedgehog (SHH/PTCH1/SMO) pathway, predominantly loss-of-function mutations in PTCH1 but also activating mutations in SMO; these genes encode two transmembrane proteins, PTCH1 (also known as Patched1) and SMO (also known as Smoothened), respectively (14, 15). The pathway is activated by the SHH signaling protein (also known as Sonic hedgehog), which binds to the extracellular domain of PTCH1, disabling inhibition of SMO; this in turn activates GLI transcription factors. Germline mutations in PTCH1 predispose patients to Gorlin syndrome (21).”
4 “In total, we identified 606 genes frequently mutated in coding regions. The most frequently mutated was PTCH1, with a total of 24 mutations in 20 BCC samples, including 5 missense, 4 splice site, and 15 deleterious (nonsense or frameshift) mutations (Figure 3A). Mutation c.3450-1G>A located upstream of exon 21 was one of the splice-site mutations and was also observed in another study (14), which suggests its recurrence in BCC.”
5 “A protein truncatingPTCH1 deletion in case 2864 indicated deregulation of the hedgehog signaling pathway that may have conferred sensitivity to the smoothened (SMO) inhibitor vismodegib”
6 “This was a phase I, multicenter, open-label study of oral LY2940680”
7 “Targeting the HH pathway does not seem to work in metastatic or recurrent cancers due to various factors, including HH target gene mutations, gene amplifications, immune-suppressive TME, and others. Many HH inhibitors are still under clinical trial with adaptive resistance (e.g., SMO inhibitors). Hence, understanding drug resistance and combining HH inhibitors with immune therapy need to be explored pronto”
8 “An exploratory study conducted by Leandro M. Colli et al. using cancer genomic data sets for somatic mutation profiles indicated that a significant proportion of SMO mutated patients could be benefited from a combination of immunotherapy with targeted therapy considering the mutational burden [136]. Petty A J et al. reported that vismodegib combined with anti-PD-1 antibody resulted in a synergistic reduction in liver tumors in mice (Hepa1-6 and LLC-1 tumors) by reversing M2 to M1 TAMs and increasing CD8+ T-cell trafficking into the TME”