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 1-24 are pending.
Claims 1-13, and 24 are examined herein.
Claims 14-23 are withdrawn (see restriction/election below).
Priority
This application is filed 09/11/2023, and claims the benefit of domestic priority as below:
PNG
media_image1.png
65
542
media_image1.png
Greyscale
Information Disclosure Statements
No IDS(s) received.
Election/Restrictions
Applicant elects Group I, claims 1-14, and 24, is drawn to a methods of treating or preventing genotoxic stress induced cardiac toxicity, with traverse in the reply field on 05/26/2026 is acknowledged. Claims 15-23 (Group II) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method of predicting, there being no allowable generic or linking claim.
Applicant argues that the restriction is improper because the restriction requirement as between treating and preventing does not establish that these uses constitute independent or distinct Inventions. Applicant further explains that although Applicant elects AZM198 as the inhibitor species, the election requirement between the method of treating and the method of preventing should be withdrawn because both embodiments use the same elected species, operate through the same mechanism, and differ only in timing or patient status, and examination of these embodiments together would not impose a serious burden. Applicant’s argument has been considered but is not persuasive.
This application is a US national stage application under 35 USC 371. Therefore, unity of invention practice applies, rather than the practice under 35 USC 111(a). (see MPEP 1850, MPEP 1896, and 37 CFR 1.475) Accordingly, the restriction requirement is not driven by a serious search burden, but rather by the lack of the same or corresponding special technical features. As noted in the restriction, the application contains claims directed to more than one species of the generic invention. These species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1.
In addition, the common use of inhibitors recited in claim 7 does not establish unity between the treatment and prevention embodiments. Under PCT Rule 13.1, a common feature must be a special technical feature that links the claimed inventions into a single general inventive concept. Applicant has not shown that the common use of the recited inhibitors provides such a special technical feature for both the treating and preventing embodiments.
Examiner agrees with Applicant’s explanations that “what is characterized as "prevention" versus "treatment" represents a continuum of the same therapeutic approach, differing only in the timing of administration relative to disease progression”, and that “dexrazoxane - an FDA-approved agent for anthracycline-induced cardiomyopathy - can be administered both prophylactically and after cardiac injury, with the same mechanism of action in each case”. However, dexrazoxane is one of the recited inhibitors, and the other inhibitors and dexrazoxane do not share a single core chemical structure. Instead, they belong to several distinct structural and pharmacological classes, though they are all utilized in cancer therapy and/or infection treatment. Moreover, the prevention and treatment embodiments rely on different patient conditions, disease stage, timing of administration, mechanism of action, and endpoints. Dexrazoxane is a different agent with its own mechanism and clinical record. Its use in anthracycline induced cardiotoxicity does not establish that the presently claimed inhibitors or the treatment and prevention embodiments, share a single general inventive concept. Thus, the recited inhibitors do not establish that they share a single general inventive concept under the unity standard.
Accordingly, under PCT Rule 13.1/13.2, the restriction requirement is deemed proper and is made FINAL.
Applicant elects the method of treating with AZM198 (2-thioxanthine) as the species in the reply field on 05/26/2026 is acknowledged.
Applicant asserts that the claims 1-13 are readable on the elected species. However, Examiner finds that the claims 1-13, and 24 read on the elected species. Claim 14 from Group I is withdrawn from consideration because this claim does not read on the elected species.
If the elected species is not identified in the prior art, the elected species would be allowable if
an independent claim were drafted with that species alone. (see MPEP 802.03)
The elected species was identified in the prior art. Accordingly, claims 1-13, and 24 that read on the elected species will be examined on their merits.
With respect to the elected species, the art is rejected under 35 USC 112 and 35 USC 103 below.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because:
The lines, numbers and lettering are not clean, well-defined, sufficiently dense and dark, and uniformly thick and well defined in Figure(s) 1B, 1D (top), 1F, 2C, 3A, 4B-D, 5B, 6C, 7C, and 8B-D. See 37 CFR 1.84(l) and (q). The graphs, in particular, use the same circular shape with different hatch directions and some of them overlap, making them difficult to interpret. In addition, Figure(s) 4B-D, 7C, and 8B-D lack marker definitions, and also has the issue mentioned above.
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim interpretation
Claims are interpreted in accordance with the broadest reasonable interpretation (BRI) standard
consistent with the specification (See MPEP 2111).
The phrase “the genotoxic stress-induced cardiac toxicity” is broadly interpreted as any cardiac toxicity, cardiac damage, cardiomyopathy, reduced cardiac function or cardiac injury resulting from exposure to a genotoxic stressor, including anticancer therapy, chemotherapy, anthracycline therapy, platinum therapy, topoisomerase inhibitor therapy, or ionizing radiation.
The phrase “an inhibitor of therapy-related clonal hematopoiesis (t-CH), neutrophil activation, neutrophil migration, neutrophil extracellular trap formation, neutrophil cytokine and/or chemokine production, or any combination thereof” is interpreted broadly to encompass any compound, agent, or composition that inhibits, reduces, suppresses, delays, impedes, or modulates at least one of the recited t-CH or neutrophil related functions.
With respect to claim 24, although, the claim is rejected under 35 USC 101 (see rejection below), the claim should be interpreted in light of the specification disclosure, it is generally considered improper to read limitations contained in the specification into the claims. (See In rePrater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969) and In re Winkhaus, 527 F.2d 637, 188 USPQ 129 (CCPA 1975), and MPEP 2173.05(q))
Claim Objections
Claim 5 is objected to because of the following informalities:
The phrase “doxorubicin, optionally doxorubicin” in claim 5 appears to be a typo, and given the list of options, the “optionally doxorubicin” language appears redundant since it is already an optional part of the list. Since the interpretation is that doxorubicin is a possible member of the list, no 112(b) rejection is made here.
Claim Rejections - 35 USC § 112, written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7, 12, 13, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by applicants. (see MPEP 2163.02)
An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. (Emphasis added)
Further, the MPEP states that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. (see MPEP 2161.01)
For instance, generic claim language in the original disclosure does not satisfy the written description requirement if it fails to support the scope of the genus claimed. Ariad, 598 F.3d at 1349-50, 94 USPQ2d at 1171 ("[A]n adequate written description of a claimed genus requires more than a generic statement of an invention’s boundaries.") (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1405-06); Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002) (holding that generic claim language appearing in ipsis verbis in the original specification did not satisfy the written description requirement because it failed to support the scope of the genus claimed); Fiers v. Revel, 984 F.2d 1164, 1170, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (rejecting the argument that "only similar language in the specification or original claims is necessary to satisfy the written description requirement").
As set forth in the en banc decision in Ariad Pharmaceuticals Inc. v. Eli Lilly and Company, 94 USPQ2d 1161 (Fed. Cir. 2010) at 1171, the court stated as follows:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. At 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. At 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 [25 USPQ2d 1601] (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
With respect to claims 1 and 24, the claims recite administering or using a composition comprising, an inhibitor of therapy-related clonal hematopoiesis (t-CH), an inhibitor of neutrophil activation, an inhibitor of neutrophil migration, an inhibitor of neutrophil extracellular trap formation, an inhibitor of neutrophil cytokine and/or chemokine production, or any combination thereof, for treating or preventing genotoxic stress-induced cardiac toxicity and related cardiac toxicity conditions. The claims define a broad functional genus of inhibitors based on biological activity rather than by a common structure, target class, chemical class, or common identifying property.
The specification does describe certain exemplary inhibitors and narrow embodiments. For example, the specification describes CXCR inhibitors, including SB225002, SB265610, and repertaxin, and states that these inhibitors reduce neutrophil influx to the hearts of doxorubicin treated mice and reversed doxorubicin effects on cardiac wall thinning and function. The specification also identifies MPO inhibitors, including AZM198, and states that such inhibitors reduce or impede a described function or pathway. However, the claims do not limit the inhibitors to those specific inhibitors or class. Instead, claims 1 and 24 encompass any inhibitor of therapy-related clonal hematopoiesis (t-CH), neutrophil activation, neutrophil migration, neutrophil extracellular trap formation, neutrophil cytokine and/or chemokine production, or any combination thereof. Accordingly, based on the reasoning below, the specification does not reasonably convey that the inventors have possession of the full scope of this broad functional genus. The absence of representative species across the full claimed genus, or disclosed or known structure function or mechanism function correlation applicable to the full genus, further reflects that the inventors are not in possession of the claimed scope at the time of filing.
Sano et al. (Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome, J. Am. Coll. Cardiol., 71(8), 875-886, pub’d 02/27/2019) teaches that TET2-mediated clonal hematopoiesis accelerates heart failure through a particular mechanism involving elevated IL-1β/NLRP3 inflammasome signaling (abstract and discussion). Thus, Sano shows that the clonal hematopoiesis heart failure relationship is pathway specific and tied to a particular inflammatory mechanism (discussion), not that all inhibitors of t-CH or all downstream inflammatory pathways would be expected to treat or prevent genotoxic stress induced cardiac toxicity. Moreover, Antonelou et al. (Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN, J. Am. Soc. Nephrol., 31(2), 350-364, pub’d 12/26/2019) teaches that therapeutic myeloperoxidase inhibition with AMZ198 reduces particular neutrophil related functions, including ROS production, neutrophil degranulation, NET formation, and neutrophil mediated endothelial damage, in the context of ANCA associated vasculitis/crescentic glomerulonephritis (abstract, and results). Thus, Antonelou supports that neutrophil inhibition is target specific and disease context specific.
In view of the pathway specific and target specific nature of the field as evidenced by Sano and Antonelou, the specification does not provide representative embodiments across the claimed functional genus or provide a credible correlation demonstrating that the broadly described inhibitor function identifies a genus that a person skilled in the art would recognize as being possessed by the inventor. The current specification may reasonably convey possession of certain disclosed species or narrower inhibitor classes such as particular CXCR2 inhibitors or particular MPO inhibitors, as discussed above, but not the full functional genus of claims 1 and 24.
With respect to claim 2-7, 12, and 13, the claim recites that cardiac toxicity resulting from a broad range of anti-cancer therapies and agents, including chemotherapeutic agents, anthracyclines, platinum compounds, topoisomerase inhibitors, ionizing radiation, and combinations thereof. Merely reciting these classes of agents and therapies does not reasonably convey possession of treating or preventing cardiac toxicity resulting from the full scope of those agents and therapies using the full genus of inhibitors recited in claim 1.
As disused above, Sano shows that chemotherapy induced cardiotoxicity depends on the particular anticancer drug and mechanism of injury. Moreover, Csapo et al. (Chemotherapy-Induced Cardiotoxicity: Pathophysiology and Prevention, Clujul. Med., 87(3), 135-42, pub’d 08/05/2014) teaches that chemotherapy induced cardiotoxicity involves different anticancer drugs and mechanisms and focuses on different mechanisms of cardiac toxicity and prevention strategies for anticancer drugs, and Csapo further shows that chemotherapy induced cardiotoxicity depends on the particular anticancer drug and mechanism of injury (abstract, antineoplastic drugs and cardiotoxicity mechanisms, and prevention section). These teachings supports that cardiotoxicity is pathway specific, target specific, and therapy dependent. Further, the recited compounds in claim 7 are heterogeneous and include compounds with different structures, clinical uses, and toxicity profiles. Some are anticancer topoisomerase Inhibitors (e.g., irinotecan, topotecan, etoposide and teniposide), while others belong to entirely different drug classes or are used in different therapeutic contexts. For example, moxifloxacin and grepafloxacin are antibacterial topoisomerase inhibitors and are associated with QTc interval prolongation, which can trigger severe ventricular arrhythmias. Further, radiation induced cardiac injury involves distinct mechanisms and time courses, including vascular/endothelial injury, inflammation, oxidative stress, fibrosis, and tissue remodeling, which differ from doxorubicin associated cardiac toxicity and from TET2-mediated clonal hematopoiesis associated heart failure.
In view of the therapy dependent nature of cardiotoxicity, as evidenced by Sano, and Csapo, broad platinum compounds, heterogeneous topoisomerase inhibitors, and therapies that are recited and/or encompassed by the claims, the disclosure of selected chemotherapy or doxorubicin related embodiments does not reasonably convey possession of the full scope of claimed therapy and agent related limitations. Although, the specification provides detailed working examples for a doxorubicin /CXCR2 inhibitor embodiment, the specification does not provide sufficient representative examples for the full scope of the recited anticancer therapies, immunomodulatory agents, anthracyclines, platinum compounds, topoisomerase inhibitors, ionizing radiation, and combinations thereof. Thus, the specification is not sufficient to show possession of the full scope of the therapy and agent related limitations recited in claims 2-7, 12 and 13.
As set forth in the en banc decision in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010), to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. (see MPEP 2161.01).
Accordingly, in view of the breadth of the claimed functional genus, the lack of representative examples, and the lack of a sufficient mechanism function or structure function correlation showing possession of a method for treating or preventing cardiac toxicity caused by the full scope of the diverse agents using the full functional genus of inhibitors recited in claim 1, as discussed above, the specification does not reasonably convey to those skilled in the art that the inventors are in possession of the full scope of claims 1-7, 12, 13, and 24 at the time of filing.
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 9, 11, and 24 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.
Regarding claim 9, the phrase "associated with" renders the claim indefinite because it is unclear
whether the limitations following the phrase are part of the claimed invention. The term "associated with" 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. Thus, the phase “associated with an inflammatory response” is unclear whether the inflammatory response must cause, result from, accompany or merely correlate with the cardiac toxicity.
Regarding claim 11, the phrases "relatively young" and “other known cardiovascular risk factors”
renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. The claim does not specify the age range or comparator population used to determine whether a cancer survivor is “relatively young”. Further, “other known cardiovascular risk factors” does not identify which cardiovascular risk factors are excluded.
Regarding claim 24, a “Use of a composition” without reciting the acts or steps required to define
a method of treatment. It is unclear whether the claim is intended to be drawn to a method, a composition, or a use of a composition.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 24 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claim recites a “use of” per se. In particular, claim 24 merely recites a “use of” a composition without reciting any affirmative step by which the use is carried out.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Although the claims 1-7, 12, 13, and 24 are rejected under 35 USC 112 for lack of written description, this 35 USC 103 rejection applies to the elected species, namely AZM198.
Claim(s) 1-5, 8-10, 12, and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wengrofsky et al. (Heart Failure and Malignancy: Implications of Chemotherapy and Radiation in the Pathogenesis of Cardiomyopathy in Cancer Treated Population, J. Cardiol & Cardiovasc. Ther. 16(4), 54-64, pub’d 12/18/2020) in view of Sano et al. (Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome, J. Am. Coll. Cardiol., 71(8), 875-886, pub’d 02/27/2019), and further in view of Antonelou et al. (Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN, J. Am. Soc. Nephrol., 31(2), 350-364, pub’d 12/26/2019).
With respect to independent claim 1, the claim recites that a method for treating or preventing genotoxic stress-induced cardiac toxicity, the method comprising administering to a subject in need thereof an effective amount of an inhibitor of therapy-related clonal hematopoiesis (t-CH), neutrophil activation, neutrophil migration, neutrophil extracellular trap formation, neutrophil cytokine and/or chemokine production, or any combination thereof.
Wengrofsky teaches that 1) cardio-oncology concerns cardiomyopathy and congestive heart failure associated with malignancy and cancer treatment (abstract, and introduction), 2) “known cardiotoxic profiles of cancer related therapies including chemotherapy, targeted antineoplastic agents, and radiotherapy” are recognized in cardio-oncology (introduction), 3) the direct cardiomyocyte effects associated with chemotherapy, immunotherapy, other targeted antineoplastic agents, and radiotherapy, and congestive heart failure (introduction), and 4) doxorubicin and other anthracyclines as etiologies of initially unexplained cardiomyopathies (introduction). Thus, Wengrofsky teaches the cancer therapy associated cardiac toxicity context, including cardiomyopathy and congestive heart failure associated with chemotherapy and radiation.
Wengrofsky fails to teach administering an inhibitor or therapy related clonal hematopoiesis, neutrophil activation, neutrophil migration, neutrophil extracellular trap formation, or neutrophil cytokine and/or chemokine production.
Sano teaches that 1) clonal hematopoiesis caused by TET2-deficient hematopoietic cells contributes to cardiac dysfunction and heart failure through an inflammatory mechanism involving IL-1β/NLRP3 inflammasome signaling (abstract, and introduction), 2)TET2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure as a results of elevated IL-1β signaling (abstract), and 3) treatment of the inflammatory mechanism using an inhibitor, including NLRP3 inflammasome inhibition, to reduce or protect against heart failure caused or accelerated by clonal hematopoiesis (abstract, and discussion). Accordingly, Sano teaches that clonal hematopoiesis related inflammatory signaling contributes to cardiac dysfunction and provides a reason to target inflammatory pathways associated with clonal hematopoiesis in cardiac dysfunction.
The combination of Wengrofsky and Sano fail to teach administering AZM198 or a myeloperoxidase inhibitor as an inhibitor of neutrophil activation or neutrophil extracellular trap formation.
Antonelou teaches that 1) therapeutic myeloperoxidase inhibition using AZM198 (abstract and introduction), 2) AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage (introduction, and discussion), and 3) delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses in an in vivo studies (introduction, and discussion). Thus, Antonelou teaches AZM198 as an MPO inhibitor that inhibits neutrophil activation related injurious functions, including NET formation and ROS production.
It would have been obvious to a PHOSITA at the time of the invention to treat or prevent genotoxic stress induced cardiac toxicity in a subject in need thereof by administering an effective amount of an inhibitor of neutrophil activation and/or neutrophil extracellular trap formation, such as AZM198, because Wengrofsky teaches that chemotherapy, anthracyclines, doxorubicin, immunotherapy, targeted antineoplastic agents, and radiotherapy are associated with cardiomyopathy and congestive heart failure in cancer treated populations, Sano teaches that clonal hematopoiesis associated heart failure is mediated by inflammatory signaling and can be improved by inhibitor treatment, and Antonelou teaches that AZM198 provides the advantage of reducing neutrophil activation related injurious functions, including ROS production, neutrophil degranulation, NET formation, and neutrophil mediated endothelial damage. Accordingly, combination the teachings of Wengrofsky, Sano, and Antonelou would have predictably provided the improvement of reducing inflammatory neutrophil mediated injury in the setting of cancer therapy associated cardiac toxicity.
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Alternatively, applying KSR example rationale (A) in the independent claim 1, it would have been prima facie obvious to administer AZM198 in the cancer therapy associated cardiac toxicity setting taught by Wengrofsky, Sano and Antonelou, because Wengrofsky provides the known cancer therapy associated cardiac toxicity setting, and Sano provides the known inflammatory cardiac dysfunction/clonal hematopoiesis pathway. Further, Antonelou provides the known AZM198/MPO inhibition approach for reducing neutrophil activation related injurious functions. The combination merely applies a known anti-inflammatory/neutrophil inhibitory agent to a known inflammatory cardiac injury context to obtain the predictable result of reducing inflammatory neutrophil mediated cardiac injury. (see MPEP 2141 and 2143)
With respect to claims 2-5, and 12, the claims further limit the genotoxic stress induced cardiac toxicity or the subject in need thereof to cardiac toxicity associated with antitumor and/or anticancer therapies, chemotherapy induced cardiac toxicity or heart damage, anthracycline associated cardiac toxicity, specific anthracyclines including doxorubicin, and ionizing radiation associated cardiac toxicity.
As discussed above with respect to claim 1, Wengrofsky teaches cancer therapy associated cardiomyopathy and congestive heart failure, including cardiac toxicity associated with chemotherapy, anthracyclines, doxorubicin, targeted antineoplastic agents, immunotherapy, and radiotherapy (introduction, pre-, peri-, and post-treatment approach to cardiotoxic chemotherapy, and anthracyclines section, and table 1 and 2). Therefore, Wengrofsky teaches the cancer therapy associated cardiac toxicity context recited in claims 2-5, and 12, including chemotherapy, anthracycline, doxorubicin, and radiation associated cardiac toxicity, as the same rational set forth above with respect to claim 1.
With respect to claims 8-10, the claims further characterize the cardiac toxicity as involving cardiac dysfunction phenotypes and/or inflammatory responses.
Wengrofsky fails to teach the cardiac toxicity as involving cardiac dysfunction phenotypes and/or inflammatory responses.
Sano teaches that cardiac dysfunction associated with clonal hematopoiesis and inflammatory signaling (abstract and discussion). Antonelou further teaches that AZM198 reduces neutrophil mediated inflammatory injury by reducing MPO dependent neutrophil functions, including ROS production, degranulation, and NET formation. Therefore, the combination teaches obvious cardiac toxicity associated with cardiac dysfunction and inflammatory response, including an inflammatory response comprising induction or elevation of IL-1β, as recited in claims 9 and 10.
Specifically, in claim 8, to the extent the claim requires reduction in cardiac contractility, tinning of ventricular wall, a reduction in cardiomyocyte size, or any combination thereof, these are conventional phenotypic manifestations or measurable endpoints of cardiac injury and dysfunction in cardiomyopathy/heart failure models. A person of ordinary skill in the art would have reasonably used such endpoints when evaluating cancer therapy associated cardiomyopathy as taught by Wengrofsky, particularly in view of Sano’s teaching of inflammatory cardiac dysfunction. Such assessment would have involved routine evaluation of known cardiac dysfunction endpoints and would have yielded predictable results. (See MPEP 2141, and 2143)
With respect to claim 24, the claim recites that the use of a composition comprising an inhibitor of therapy-related clonal hematopoiesis (t-CH), an inhibitor of neutrophil activation, an inhibitor of neutrophil migration, an inhibitor of neutrophil extracellular trap formation, an inhibitor of neutrophil cytokine and/or chemokine production, or any combination thereof for treating or preventing genotoxic stress-induced cardiac toxicity, chemotherapy-induced cardiac toxicity, chemotherapy-induced heart damage, or chemotherapy-induced reduction in cardiac function.
The claim is interpreted as requiring the therapeutic use corresponding to the method of claim 1, the same rationale set forth above for claim 1. It would have been obvious to use a composition comprising an inhibitor of neutrophil activation and/or NET formation, such as AZM198, for treating or preventing genotoxic stress induced cardiac toxicity, chemotherapy induced cardiac toxicity, chemotherapy induced heart damage, or chemotherapy induced reduction in cardiac function, because the combination would have predictably provided the advantage of reducing inflammatory, neutrophil mediated injury in a cancer therapy associated cardiac toxicity setting. (See MPEP 2141, and 2143)
Claim(s) 6, 7, 11, and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wengrofsky et al. (Heart Failure and Malignancy: Implications of Chemotherapy and Radiation in the Pathogenesis of Cardiomyopathy in Cancer Treated Population, J. Cardiol & Cardiovasc. Ther. 16(4), 54-64, pub’d 12/18/2020), Sano et al. (Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome, J. Am. Coll. Cardiol., 71(8), 875-886, pub’d 02/27/2019), and Antonelou et al. (Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN, J. Am. Soc. Nephrol., 31(2), 350-364, pub’d 12/26/2019). as applied to claims 1, 4, and 9 above, and further in view of Csapo et al. (Chemotherapy-Induced Cardiotoxicity: Pathophysiology and Prevention, Clujul. Med., 87(3), 135-42, pub’d 08/05/2014).
The combination teachings of Wengrofsky, Sano, and Antonelou fail to teach the additional limitations of claims 6, 7, 11, and 13, including the recited platinum compounds, topoisomerase inhibitor, subject limitation, and exposure limitation.
With respect to claim 6, the claim recites that the platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin, or any combination thereof.
Csapo teaches that chemotherapy induced cardiotoxicity is associated with additional cytostatic agents, including alkylating/platinum type agents such as cisplatin and carboplatin (abstract, and antineoplastic drugs and cardiotoxicity mechanisms section). For the same rationale set forth above with respect to claim 1, and further in view of Csapo’s teaching that platinum type chemotherapeutic agents are associated with cardiotoxicity, it would have been obvious to apply the claimed method to cardiac toxicity associated with platinum compound, including cisplatin or carboplatin, with a reasonable expectation of reducing inflammatory, neutrophil mediated cardiac injury. (see MPEP 2141, 2143, and 2143.02)
With respect to claim 7, the claim recites that the topoisomerase inhibitor is selected from the group consisting of teniposide, irinotecan, etoposide, topotecan, mitoxantrone, moxifloxacin, grepafloxacin, dexrazoxane, valrubicin, and epirubicin, or any combination thereof.
Csapo teaches that chemotherapy induced cardiotoxicity may occur with cytostatic agents beyond anthracyclines, and discusses anticancer drug cardiotoxicity involving topoisomerase related mechanisms in cardiotoxicity (antineoplastic drugs and cardiotoxicity mechanisms and prevention section). Csapo further teaches the dexrazoxane that is anticancer agents associated with anthracycline/anthracenedione type chemotherapy and topoisomerase related anticancer activity (cardioprotective drugs section).
With respect to claim 11, the claim recites that the subject is a cancer survivor who is relatively young and/or does not have other known cardiovascular risk factors.
Csapo teaches patient related risk factors for chemotherapy induced cardiotoxicity, including age, female gender, pre-existing cardiovascular disorders, electrolyte imbalance, concurrent cardiotoxic agents, and prior anthracycline chemotherapy (Identifying patients at risk section).
Accordingly, Csapo teaches that cardiovascular risk factors are relevant to chemotherapy induced cardiotoxicity, while Wengrofsky teaches that cancer therapy itself may be associated with cardiomyopathy and congestive heart failure in cancer treated populations, as disused above (introduction). It would have been obvious to apply the claimed method to a cancer survivor who is relatively young and/or does not have other known cardiovascular risk factors. A person of ordinary skill in the art would have recognized that relatively young cancer survivors and/or does not have other known cardiovascular risk factors could be subjects in need of treatment or prevention where cardiac toxicity is associated with prior cancer therapy exposure. In view of Sano’s inflammatory cardiac dysfunction teaching and Antonelou’s AZM198/neutrophil inhibitory teaching, such treatment would have had a reasonable expectation of reducing inflammatory, neutrophil mediated cardiac injury in such cancer survivors. (see MPEP 2143 and 2143.02)
With respect to claim 13, the claim recites that the genotoxic stress-induced cardiac toxicity results from exposure to a platinum compound, a topoisomerase inhibitor, or any combination thereof.
Csapo teaches that platinum type agents, including cisplatin and carboplatin, are chemotherapeutic agents associated with cardiotoxic side effects, and further teaches that chemotherapy induced cardiotoxicity may involve additional cytostatic agents and topoisomerase related anticancer mechanisms (antineoplastic drugs and cardiotoxicity mechanisms section). Therefore, Csapo teaches obvious that cancer therapy associated cardiac toxicity may result from exposure to platinum compound, a topoisomerase inhibitor, or a combination thereof, as the same set forth above with respect to claim 1.
Conclusion
Claims 1-13, and 24 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights