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 .
Status of the Claims
Claims 7-8, 15, 18-23 and 25-37 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/EP2020/058362, filed on 03/25/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/03/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The prior rejection of claims 1, 7, 8, 15, 18-20, 25, 26, 30-32 and 34 under 35 U.S.C. 103 as being unpatentable over Incyte Corporation ("Azacitidine Combined With Pembrolizumab and Epacadostat in Subjects With Advanced Solid Tumors (ECHO-206)", ClinicalTrials.gov, Identifier NCT02959437)1, in view of Muñoz (US Patent 9,670,136 B2) is maintained. Applicant has traversed this argument on the basis that the combination of iadademstat with a PD-1 or PD-L1 inhibitor could not be reasonably expected by a person of ordinary skill in the art because Applicant has discovered an unexpected synergy in therapeutic effect, and has provided the following assertions regarding the determination of this synergy:
Isobolograms, based on the method of Loewe, are practical for in vitro evaluations and not for in vivo assays because the abundance of data needed for statistical rigor of the isobologram approach is in conflict with the ethical limit on sacrifice of live subjects to provide data;
Bliss independence and Highest Single Agent (HSA) are more appropriate models for the evaluation of synergy in combination therapy in the context of tumor growth suppression;
Both Bliss Independence and HSA assert independence when the combination index (CI) value obtained from data is < 1.
Data from tumor growth inhibition studies provided in Applicant’s Experimental Report (provided via of the parent PCT application) provide CI values below 1 by each of the Bliss and HSA models employed.
Applicant’s assertions have been evaluated. The Examiner accepts that an alternate evidentiary means to demonstrate synergy can potentially serve for in vivo experiments. However, Applicant’s assertion of synergy based on combination index (CI) values reported for data from the prior Experimental Report is not found persuasive, for the following reasons:
Highest Single Agent analysis does not assert synergy (superadditive behavior) for all CI values below 1, but rather merely attests additive behavior, per the teaching of Duarte_2022 (Duarte, D., and Vale, N.; Current Research in Pharmacology and Drug Discovery, v3, Article 100110, pp.1-13; 2022);
Bliss Independence is prone to false positives when the combination effect is not averaged across the results, per the teaching of Zhao (Zhao, et al.; Journal of Biomolecular Screening, v19, pp.817-821; 2014);
Applicant’s provision of CI values for in vivo assays of combination therapy comprising iadademstat and a PD-L1 inhibitor is incomplete:
Applicant has provided neither the mathematical process used, nor a particular reference thereof, and has not provided any numerical data when the prior report of the same data in the Experiment Report is only graphical;
Applicant provided CI values only for isolated data points of studies provided in the Experimental Report. No rationale has been provided, for example, to evaluate the CI for the combination study on melanoma only on the final day of treatment and not other timepoints, nor for evaluating the small cell lung cancer xenografts on precisely day 7 of a >30 day study (shown below). The CI should be evaluated independently, or as an average, across all timepoints of the study, or a rationale to not do so should be provided.
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Duarte teaches a review of various models of assessing synergism in drug combinations and reference models for oncology, including both effect-based models such as Bliss Independence and Highest Single Agent (HSA), as well as dose-effect models such as Loewe Additivity. Duarte teaches that HSA assumes a positive combination interaction when the drug combination elicits a greater response than the highest single agent and, for a binary combination, follows the equation
C
I
=
max
(
E
A
,
E
B
)
E
A
B
wherein “max (EA, EB)” represents the highest response from either single agent in the combination, and EAB represents the response from the combination. Duarte further teaches that this model only compares the drug combination effect to the most effective individual drug (highest single agent), not taking into account the expected additive effect of both drugs involved in the combination. This makes this model suitable only for drug combinations where one of the drugs is inactive (as a single agent) for all tested concentrations (page 4). Thus, HSA is not a suitable model of synergism for the combination of an LSD1 inhibitor with a checkpoint inhibitor, as each of these agents is active as a single agent.
Zhao teaches that Bliss Independence follows the equation
Y
a
b
,
P
=
Y
a
+
Y
b
-
Y
a
Y
b
wherein “Yab,P” represents the predicted combination therapy response in, for example, inhibition of tumor growth from agents “a” and “b”, and “Ya” and “Yb” represent the individual response achieved by each of these agents as a single agent (page 817). The implications of the equation, being basic algebra, are readily envisaged by a person of ordinary skill in the art: the subtraction of the product “YaYb” from the added individual response (Ya + Yb) represents the recognition that an additive response must account for the overlap in affectable population of, for example, tumor cells. If one agent is affecting, and thereby depleting/inhibiting the initial population of tumor cells, then the response from the second agent will be less than if that second agent were administered as a single agent. Zhao teaches that if the observed combination response is greater than the predicted combination response, then the combination is synergistic, and that typically the comparison is examined at each dose combination. Average percentage inhibition is usually used when replicates are available and a conclusion can be drawn by strictly following the mathematical relations. But performing tests repetitively at all combination doses becomes a multiple testing problem, which easily leads to false-positive claims (page 818). Thus, Applicant’s provision of CI values at a single selected timepoint for each in vivo assay on tumor growth inhibition lacks rigor and is therefore unpersuasive as an assertion of synergy.
Reiterated Rejection:
Claims 1, 7, 8, 15, 18-20, 25, 26, 30-32, and 34 are unpatentable over Incyte Corporation, in view of Muñoz.
Claims 1, 7, 8, 15, 18-20, 25, 26, 30-32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Incyte Corporation ("Azacitidine Combined With Pembrolizumab and Epacadostat in Subjects With Advanced Solid Tumors (ECHO-206)", ClinicalTrials.gov, Identifier NCT02959437)2, in view of Muñoz (US Patent 9,670,136 B2).
Regarding instant claims 1, 7, 8, 15, 18-20, 25, and 26, Incyte Corporation teaches a method of treating melanoma comprising administering a combination comprising an LSD1 inhibitor (INCB059872) and a PD-1 inhibitor (pembrolizumab) (Record History, Page 9). Incyte Corporation does not teach the use of iadademstat as the LSD1 inhibitor.
However, Muñoz teaches that iadademstat is a potent inhibitor of LSD1 and therefore can be useful for the treatment or prevention of any disease associated with LSD1, and specifically claims iadademstat (by its IUPAC name) for the treatment of cancer. Muñoz teaches that iadademstat can be administered in combination with another active agent that synergistically treats or prevents the same symptoms, including anti-cancer drugs (Col. 95, lines 57-67), including anti-cancer drugs that are antibodies (Col. 99, lines 38-44). Muñoz teaches that such combination administration can be done simultaneously (e.g., in a single formulation) or separately, including oral and intravenous routes (Col. 96, lines 1-12).
Since Incyte Corporation teaches a combination of an LSD1 inhibitor (INCB059872) with a PD(L)1 inhibitor (pembrolizumab), and Muñoz teaches that iadademstat is a potent inhibitor of LSD1, before the effective filing date of the invention, it would have been prima facie obvious for a person of ordinary skill in the art to substitute one functional equivalence (INCB059872) for another (iadademstat) with a reasonable expectation of success.
Taken together, all this would result in the practice of the method of claims 1, 7, 8, 15, 18-20, 25, and 26 with a reasonable expectation of success.
Regarding claims 30 and 31, Incyte Corporation teaches the combination is administered separately, LSD1 inhibitor is administered orally and pembrolizumab administered by intravenous infusion (Record History, page 11, right panel). It would have been prima facie obvious, in view of the teachings of Incyte, to (1) administer iadademstat orally and to (2) administer iadademstat and pembrolizumab separately, with a reasonable expectation of success.
Regarding claim 32, Incyte Corporation does not teach administering the LSD1 inhibitor and PD1 inhibitor as a simultaneous regimen. However, Muñoz teaches iadademstat can be administered in combination with another active and such combination administration can be done simultaneously (e.g., in a single formulation) or separately, including or and intravenous routes (col 96, lines 1-12). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to administer the combination of iadademstat and PD1 inhibitor simultaneously or separately in view of the teachings of the prior art, resulting in the method of claim 32 with a reasonable expectation of success.
The rejection of claim 29 under 35 U.S.C. 103 is maintained. Applicant has traversed the prior rejection, citing the same argument of unexpected results for the instant application as presented for the rejection above. The response to Applicant’s assertion of synergistic results has been discussed in the rejection above and is hereby incorporated into the instant rejection. Applicant has also traversed the prior rejection on the basis that a person of ordinary skill in the art would have no motivation to select iadademstat hydrochloride above any other LSD1 inhibitor for a simple substitution of the LSD1 inhibitor INCB059872 to obtain a predictable result without hindsight reasoning based on the results disclosed in the instant application. This argument has been considered but is not found persuasive, because the prior rejection included the rationale that a person of ordinary skill in the art would be particularly motivated to use iadademstat dihydrochloride due to its properties disclosed by Diodone: its unexpected stability relative to other dihydrochloride salts of active pharmaceutical ingredients and its ease of detectability even at very lose dose in pharmaceutical compositions, by means of Raman spectroscopy.
Reiterated Rejection:
Claim 29 is rejected as being unpatentable over Incyte Corporation in view of Diodone.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Incyte Corporation, in view of Diodone (Published PCT application WO 2016/177656 A1).
Incyte Corporation teaches the administration of a combination comprising an LSD1 inhibitor (INCB059872) and a PD-1 inhibitor (pembrolizumab), as a method for treating cancer in human patients in need thereof (subjects with advanced or metastatic solid tumors), including human patients with melanoma (Record History, Page 9). Incyte Corporation does not teach the use of iadademstat di-hydrochloride as the LSD1 inhibitor. Diodone teaches the use of the di-hydrochloride salt of iadademstat as an LSD1 inhibitor (claim 38), including in combination with other therapeutic agents relevant to LSD1-modulated illness, including cancer (Col. 28, lines 9-16). Diodone teaches that iadademstat di-hydrochloride exhibits a surprising stability relative to other di-hydrochloride salts of active pharmaceutical ingredients, which typically decompose and release corrosive hydrochloric acid (Col. 3, lines 8-13). The ”Form B” polymorph of iadademstat di-hydrochloride remains stable in high humidity is thermally stable up to 210°C (Col. 12, lines 4-9). Additionally, the “Form B” polymorph has particular Raman band signals that allow for detection of this highly potent active pharmaceutical ingredient component in a formulation even at very low dose (Col. 17, line 22 – Col. 18, line 6).
Since Incyte Corporation teaches a combination of an LSD1 inhibitor (INCB059872) with a PD(L)1 inhibitor (pembrolizumab), and Diodone teaches that iadademstat di-hydrochloride is a useful inhibitor of LSD1, at the time of the invention it would have been prima facie obvious for a person of ordinary skill in the art to substitute one functional equivalence (INCB059872) for another (iadademstat dihydrochloride) with a reasonable expectation of success. One would be particularly motivated to use iadademstat dihydrochloride due to its unexpected stability relative to other dihydrochloride salts of active pharmaceutical ingredients, as well as due to its ease of detectability even at very lose dose in pharmaceutical compositions, by means of Raman spectroscopy.
The prior rejection of claims 7-8, 15, 18-23 and 25-37 as being unpatentable under 35 U.S.C. 103 as being unpatentable over Incyte Corporation in view of Shi (US 2020/0255527 A1) and further in view of Muñoz is maintained. Applicant has traversed the rejection on the basis of two arguments:
A person of ordinary skill in the art would not have reasonably expected to combine the teaching of Incyte Corporation with the disclosures of Shi and Muñoz to achieve the (alleged) synergistic result disclosed by the instant application.
A person of ordinary skill in the art would not reasonably expect that results achieved by the combination of genetic knockdown of LSD1 with a checkpoint inhibitor disclosed by Shi could be matched by a combination of iadademstat with a checkpoint inhibitor because prior art provides a cautionary example against the interchangeability of different forms of LSD1 inhibition, in the form of Bandini (Bandini, et al.; Experimental Hematology & Oncology, v12, Article 71, pp1-17; 2023), who shows that irreversible and/or active site-directed LSD1 inhibitors perform poorly compared to reversible allosteric LSD1 inhibitors or genetic silencing of LSD1, when tested in combination with carfilzomib, a proteasome inhibitor, for treatment of multiple myeloma.
Applicant’s arguments have been considered, but are not found persuasive, for the following reasons:
The response to Applicant’s assertion of synergistic results has been discussed in the rejection above and is hereby incorporated into the instant rejection;
The assertion of unexpected synergy in the combination of iadademstat and a checkpoint inhibitor pre-supposes that the prior art does not teach or suggest such synergy; however, Shi teaches not only an expectation of synergy but actual synergistic results in the combination of LSD1/checkpoint inhibition, as discussed in the prior rejection;
An assertion that prior art teaches away from the claimed invention would require support by art that meets the condition of “prior art” under U.S.C. § 102; the report by Bandini, published in 2023, does not meet the filing date of the instant application and is therefore not valid prior art under U.S.C. § 102;
An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness: see In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979), wherein Bandini’s results comparing different classes of LSD1 inhibition are taught for a different form of cancer (multiple myeloma, a blood cancer) and for a combination with a different class of chemotherapeutic agent (carfilzomib, a proteasome inhibitor, rather than a checkpoint inhibitor) and are therefore not found to be a persuasive argument that a person of ordinary skill in the art would discount the probability of success of an irreversible LSD1 inhibitor (such as iadademstat) being effective against a melanoma or carcinoma when used in a method of treatment in combination with a checkpoint inhibitor. The comparison of Bandini’s results to the instantly disclosed results is not an “apple to apples” match up. Bandini does not teach or suggest that reversible and/or allosteric LSD1 inhibitors will always succeed in combination therapies against cancer while irreversible enzymatic LSD1 inhibitors will fail; rather, Bandini makes a specific observation for superior efficacy of reversible and/or allosteric LSD1 inhibitors over irreversible enzymatic LSD1 inhibitors in a specific combination with Carfilzomib, a proteasome inhibitor that is distinct from the inhibitor class of the additional agent of the claimed invention, which are checkpoint inhibitors, and Bandini’s observations are in the context of treatment of multiple myeloma, a specific cancer type that is distinct from the applicable cancer types of the claimed invention. Bandini does not teach any basis for the results observed therein or pose any hypothesis to explain the results, and does not suggest that equivalent results are likely to be observed in any other combination therapy comprising an LSD1 inhibitor and/or against any other cancer type besides multiple myeloma. Therefore, a person of ordinary skill in the art would have no motivation to apply the observation of Bandini to other contexts.
Applicant’s assertion that genetic knockdown of LSD1 as demonstrated by Shi cannot be comparable to irreversible small molecule inhibition of LSD1 is not supported by the prior art, as evidenced by Augert_2019 (Augert, et al.; Science Signalling, v12, Article eaau2922, pages 1-15; 2019). Augert_2019 reports on a study of treatment of small-cell lung cancer (SCLC) using iadademstat (“ORY-1001”) in comparison to genetic knockdown of LSD1 and shows comparable results. Augert_2019 teaches that LSD1 inhibition activates the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis, and that the effects of pharmacological LSD1 inhibition using ORY-1001 (iadademstat) were confirmed by knockdown studies (Abstract, page 1). Augert_2019 specifically reports that ex vivo treatment of patient-derived xenograft (PDX) SCLC cancer cells with ORY-1001 showed strong sensitivity of the PDX cells to inhibition with the small molecule LSD1 inhibitor, and gene ontology analyses of the PDX cells showed upregulation of NOTCH while suppressing ASCL1 (page 3), and that genetic knockdown of LSD1 in an SCLC cell line using lentiviral short hairpin RNA (shRNA) resulted in increased abundance of NOTCH1 and decreased abundance of ASCL1, as well as reduced cell viability (bridging paragraph, pages 3 to 5, interrupted by graphs on page 4). Thus, prior art shows that in a cancer relevant to the instant claims, inhibition of LSD1 by iadademstat, in particular, is comparable to the effects of genetic knockdown of LSD1.
Reiterated Rejection:
Claims 7-8, 15, 18-23 and 25-37 are unpatentable over Incyte Corporation in view of Shi and Muñoz.
Claims 7-8, 15, 18-23 and 25-37 are rejected under 35 U.S.C. 103 as being unpatentable over Incyte Corporation in view of Shi (US 2020/0255527 A1) and further in view of Muñoz.
Claims 7-8 are each drawn to a method of treating a cancer comprising administering iadademstat (or a pharmaceutically acceptable salt or solvate thereof) and a PD(L)1 inhibitor.
Incyte Corporation teaches a method of treating melanoma comprising administering a combination comprising an inhibitor of Lysine Specific Demethylase 1 (LSD1), designated as INCB059872, with pembrolizumab, an antibody PD-1 inhibitor (Record History, Page 9). Incyte Corporation does not teach the use of iadademstat as the LSD1 inhibitor. However, a person of ordinary skill in the art would have had a reasonable expectation of success in substituting iadademstat for the INCB059872 inhibitor employed by Incyte Corporation because the treatment of cancer with a combination of an LSD1 inhibitor and a PD-1 inhibitor is a general strategy of combination treatment for cancer that was known in the art as it is taught by Shi to work independently of the selection of LSD1 inhibitor and PD-1 inhibitor, and because iadademstat is a potent inhibitor of LSD1 useful in the treatment of LSD1-associated diseases including cancers and is suitable for combination treatments including wherein the additional agent is an antibody, per the teaching of Muñoz.
Shi teaches a method of treating cancer in a patient, the method comprising administering to a patient in need of cancer treatment therapeutically effective amounts of a lysine-specific demethylase 1A (LSD1) inhibitor and at least one of a PD-1 inhibitor or a PD-L1 inhibitor (paragraph [0007]). Shi further designates examples of exemplary LSD1 inhibitors including “ORY1001” (paragraph [0015]), further described as rel-N1-[ (1R,2S)-2-phenylcyclopropyl]-1,4-
cyclohexanediamine dihydrochloride (page 14, Table 1), a salt form analogue of iadademstat (trans-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine). Shi’s ORY1001 encompasses iadademstat along with additional stereoisomers that fall under the same structural formula. Shi further specifies that an exemplary PD-1 antibody inhibitor useful in the combination treatment is pembrolizumb (paragraph [0261]). Shi includes “Example 9”, wherein mice bearing solid tumors are treated with a combination inhibition of LSD1 (by genetic knockdown) and PD-1 inhibition (using an anti-PD-1 antibody) showing that the combination treatment gives a superior effect compared to either the LSD1 inhibition or PD-1 inhibition alone (paragraph 342). This enhanced combination treatment effect on suppressing tumor growth is shown in Shi’s Figure 11C, which is at least as additive as Applicant’s data shown above.
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Muñoz teaches that iadademstat is a potent inhibitor of LSD1 and therefore can be useful for the treatment or prevention of any disease associated with LSD1, and specifically claims iadademstat (by its IUPAC name) for the treatment of cancer (Col. 91, line 64-Col. 92, line 8). Muñoz teaches that iadademstat can be administered in combination with another active agent that synergistically treats or prevents the same symptoms, including anti-cancer drugs (Col. 95, lines 57-67), including anti-cancer drugs that are antibodies (Col. 99, lines 38-44). Muñoz teaches that such combination administration can be done simultaneously (e.g., in a single formulation) or separately, including oral and intravenous routes (Col. 96, lines 1-12).
Applicant’s invention is unpatentable over the disclosure of Incyte Corporation in view of the teachings of Shi and Muñoz, because a person of ordinary skill in the art, at the time of filing, would have had a reasonable expectation of success in treating melanoma with a combination of iadademstat and pembrolizumab, because the combination of an LSD1 inhibitor with a PD-1 inhibitor was known in the art in the specific example of Incyte Corporation (INCB059872 with pembrolizumab) as well as a general strategy, per the teaching of Shi, that is not dependent on the specific identity of the LSD1 inhibitor or PD-1 inhibitor, and because Shi provides exemplary LSD1 inhibitors that includes “ORY1001” a chemical formula that encompasses the structure of iadademstat along with additional stereoisomers thereof, and because Muñoz teaches that iadademstat is an effective inhibitor of LSD1 suitable for combination treatments of diseases including cancers, including wherein the additional agent is an antibody.
Thus, the invention was prima facie obvious at the time of filing.
Claim 15 further limits the method of claim 8 to wherein the PD(L)1 inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor, and is met by the rejection above.
Claim 18 further limits the method of claim 8 to wherein the PD(L)1 inhibitor is a PD-1 inhibitor, and is met by the rejection above.
Claims 19 and 20 further limit claim 18, each to a Markush group of specific PD-1 inhibitors, each group including pembrolizumab; thus, each of claims 19 and 20 are met by the rejection above.
Claim 21 further limits claim 8 to wherein the PD(L)1 inhibitor is a PD-L1 inhibitor. As discussed in the rejection above, Shi discloses a general strategy of cancer treatment comprising the combination treatment using an LSD1 inhibitor and either a PD-1 or PD-L1 inhibitor.
Claims 22-23 further limit claim 21, each to a Markush group of PD-L1 inhibitors that include durvalumab, atezolizumab and avelumab. Shi specifically discloses that the combination treatment using an LSD1 inhibitor and a PD-1 inhibitor and/or PD-L1 inhibitor can include wherein the PD-L1 inhibitor is selected from the group of: durvalumab, atezolizumab and avelumab (paragraph [0021]).
Claim 25 further limits the method of claim 8 to a narrower genus of cancers that includes melanoma and small cell lung cancer, and is met by the rejection above.
Claim 26 further limits claim 25 to wherein the cancer to be treated is specifically melanoma, and is met by the rejection above.
Claim 27 further limits claim 25 to wherein the cancer to be treated is specifically small cell lung cancer. Shi discloses that the combination treatment using an LSD1 inhibitor and a PD-1 inhibitor and/or PD-L1 inhibitor can include treatment of a specific group of cancers that includes small cell lung cancer (paragraph [0024]).
Claim 28 further limits the method of claim 8 to wherein the cancer is refractory, non-responsive or relapsed to PD(L)1 inhibitor therapy. Shi discloses that the combination treatment using an LSD1 inhibitor and a PD-1 inhibitor includes wherein the cancer to be treated is PD-1 and/or PD-L1 refractory (paragraph [0026]).
Claims 29 and 37 further limit the methods of claim 8 and claim 7, respectively, to wherein iadademstat dihydrochloride fulfills the role of “iadademstat or a pharmaceutically acceptable salt or solvate thereof”. Claims 35 and 36 further limit the methods of claim 8 and claim 7, respectively, to wherein the combination comprises a pharmaceutically acceptable salt of iadademstat. Shi provides ORY1001, a dihydrochloride salt of the structural formula that encompasses iadademstat, while Muñoz, in addition to iadademstat, discloses the preparation of iadademstat dihydrochloride (Col. 152, lines 1-64), and discloses that the invention of LSD1 inhibitor compounds reported therein includes the pharmaceutically acceptable salt, preferably the hydrochloride salt or dihydrochloride salt, of any of the named LSD1 inhibitor compounds disclosed therein (Col. 81, lines 55-60), a list that includes iadademstat which is included by name (Col. 78, lines 48-49).
Claim 30 further limits the administration of iadademstat or its pharmaceutically acceptable salt to oral administration. Shi teaches oral administration of LSD1 inhibitors, both in principle (paragraphs [0223] and [0278]) and in practice (“Example 11”, paragraph [0345]), and Muñoz teaches oral administration of LSD1 inhibitors including iadademstat (Col. 94, lines 10-36).
Claims 31 and 32 further limit claim 8 to wherein iadademstat and the PD(L)1 inhibitor are administered using separate formulations or as a simultaneous regimen, respectively. Claim 33 further limits claim 8 to a sequential administration of the separate agents of the combination.
Shi teaches combined formulation of LSD1 inhibitor with PD-1 and/or PD-L1 inhibitor (paragraph [0224]) as well as administration of an LSD1 inhibitor via separate, sequential formulation from a PD-1 and/or PD-L1 inhibitor (paragraph [0225]). Shi demonstrates separate administrations of formulated LSD1 inhibitor (GSK2879552, delivered orally or intra-peritoneally) and an anti-PD-1 antibody (delivered separately and only intra-peritoneally). Muñoz teaches that when a compound disclosed therein is administered in a combination treatment, the agents may be administered via the same route or using different administration routes, for example one compound can be administered orally and the other intravenously, and that the administration can be simultaneous, sequential or separate (Col. 96, lines 1-12).
Claim 34 further limits claim 8 to wherein the patient is a human. Incyte Corporation demonstrations treatment of human patients with an LSD1 inhibitor (INCB059872) and a PD-1 inhibitor (pembrolizumab). Shi teaches that treatment of humans is included with animal subjects with the general combination of LSD1 inhibitor and PD-1 and/or PD-L1 inhibitor and designates humans among preferred subjects to be treated (paragraph [0048]). Muñoz indicates that “more preferably”, subjects/patients to be treated with the compounds disclosed therein are human (Col. 90, lines 44-50).
Applicant’s invention is unpatentable over the disclosure of Incyte Corporation in view of the teachings of Shi and Muñoz because a person of ordinary skill in the art, at the time of filing, would have had a reasonable expectation of success in treating melanoma or small cell lung cancer in a human patient with a combination of pembrolizumab or a PD-L1 inhibitor such as durvalumab, atezolizumab or avelumab, with iadademstat or its dihydrochloride salt, in any of the formulations and patterns and routes of administration of the instant claims, for the following reasons:
the combination of an LSD1 inhibitor with a PD-1 inhibitor was known in the art as a specific example of Incyte Corporation (INCB059872 with pembrolizumab) in the treatment of human subjects with melanoma;
the combination of an LSD1 inhibitor with a PD-1 and/or PD-L1 inhibitor was known in the art as a general strategy, per the teaching of Shi, that is not dependent on the specific identity of the LSD1 inhibitor, PD-1 inhibitor, or PD-L1 inhibitor, and is useful for the treatment of cancers including melanoma and small cell lung cancer;
Shi provides exemplary LSD1 inhibitors that includes “ORY1001” a chemical formula that encompasses the structure of iadademstat along with additional stereoisomers thereof, as a dihydrochloride salt;
Muñoz teaches that iadademstat is an effective inhibitor of LSD1 suitable for combination treatments of diseases including cancers, including wherein the additional agent is an antibody, and that the dihydrochloride salt of iadademstat or any of the other compounds disclosed by Muñoz may also be used;
The formulations, administration routes and patterns of the instant claims are all found recited by Incyte Corporation, and/or Shi, and/or Muñoz.
Thus, the invention was prima facie obvious at the time of filing.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 https://clinicaltrials.gov/study/NCT02959437?term=NCT02959437&rank=1; Record History 05Apr2018, Accessed 01Aug2024.
2 https://clinicaltrials.gov/study/NCT02959437?term=NCT02959437&rank=1; Record History 05Apr2018, Accessed 01Aug2024.