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 .
Priority
This application claims the benefit of US Provisional Application No. filed on 15 June 2023. The claim for benefit is acknowledged.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 recites the limitation,
“… wherein Y is C6-10 aryl unsubstituted or substituted with R1, C6-10 aryl unsubstituted or substituted with R1…” This specific limitation for the Y substituent, pertaining to the aryl moiety, is recited twice.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
(i) Claims 1-23 and 27-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating or preventing a flare in inflammatory conditions related to an overabundance of mast cells, is not enabled for treating or preventing a flare in inflammatory conditions unrelated to mast cells accumulation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” . . . These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed invention in turn below.
The breadth of the claim is broad in scope. The claim recites: “A method of treating an inflammatory condition or preventing a flare in the inflammatory condition in a subject in need thereof…” This method of treatment or prevention extends to all inflammatory conditions with a vast population of subjects. The specification states: “There is an urgent need for pharmacological treatments for inflammatory conditions as well as preventative measures for preventing or reducing flares in inflammatory conditions. The newly identified c-kit inhibitors described herein reduced the number of mature mast cell number or increase the ratio of immature mast cells to mature mast cells in a tissue, organ, or system of subjects who suffer from inflammatory conditions related to an overabundance of mature mast cells.” (Spec., p. 1). The claim, however, encompass a method of treating or preventing a flare in all inflammatory conditions.
The nature of the invention generally relates to the pharmaceutical art and more specifically to compounds of Formula I administered to subjects having an inflammatory condition. The instant specification states: “The tyrosine kinase c-kit (CD 117) is expressed on the surface of mast cells. Activation of c-kit leads to activation of mast cells and their subsequent release of inflammatory factors. Certain human diseases like mast cell leukemia, mastocytosis, urticaria, and Lyme disease are related to c-kit activation. Allergic reaction is a condition driven by activation of mast cells in response to environmental stimuli, e.g., pollen, dust, food, and the like. These diseases and conditions are characterized by an overabundance of mature mast cells in the blood and/or tissues that triggers prolonged or permanent immune responses.” (Spec., p.1). “Exemplary inflammatory conditions relevant to this disclosure include, but are not limited to, mastocytosis, mast cell activation syndrome, hereditary alpha tryptasemia, urticaria, Lyme disease, mast cell leukemia, chronic obstructive pulmonary disease, long COVID, asthma, inflammatory bowel disease, arthritis, allergy, and gout.” (Spec., p. 4). Thus, the nature of the invention is sophisticated.
The state of the prior art is in part discussed in an article about rheumatoid arthritis, an inflammatory condition, which states: “Rheumatoid arthritis (RA) affects millions of individuals worldwide. This chronic autoimmune disorder is characterized by immune-mediated inflammation within joint tissue. Although arthritis can in many cases improve with immunomodulatory therapies, treatment is often lifelong, and episodic flares of joint inflammation continue to affect most patients.” (Chang et al., p. 1). “Memory T cells are immune cells that develop after antigen exposure and persist for a lifetime. Resident memory T cells (TRM) develop in tissues after antigen exposure, taking up long term residence to provide local site-specific immune defense against pathogens previously encountered in these locations… They exhibit effector functions such as cytokine production and cytolysis, activation of local innate and adaptive immune cells, and recruitment of other effector cells from circulation.” (Chang et al., p. 1). Another article states: “Recently, the results of a pilot clinical study suggested that imatinib mesylate [a known c-kit inhibitor] may have significant antirheumatic activity…The reason for this potentially antirheumatic activity of imatinib is not clear, but it might be related to the inhibition of the synoviocyte PDGF receptor tyrosine kinase or the inhibition of c-kit in synovial tissue or it might be mediated by inhibition of some as yet unidentified tyrosine kinase… If the imatinib mesylate induced apoptosis and depletion of tissue mast cells can also be accomplished in vivo, it might represent a new means of examining the significance of mast cells in RA.” (Juurikivi et al., p. 1131). The state of the prior art is complex in relation to inflammatory conditions and is ascending towards the possibility of c-kit inhibitors possessing antirheumatic activity. But Examiner is unaware of evidence from the prior art that supports a claim for compounds of Formula I, that are c-kit inhibitors, treating or preventing a flare in all inflammatory conditions, like RA, wherein the pathophysiology is related to TRM and not mast cells.
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Ent. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brane, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical or veterinary medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
The amount of direction provided by the inventor includes information about the invention: “Provided herein are small molecule compounds that were newly discovered to be c-kit inhibitors. Also disclosed are compositions and pharmaceutical formulations containing a compound described herein. Additionally, methods of treating or preventing an inflammatory condition, disorder, or disease or conditions, disorders, or diseases associated with an overabundance of mature mast cells using the compounds, compositions, or pharmaceutical formulations are disclosed. Such conditions, disorders, or diseases include, but are not limited to, mastocytosis, mast cell activation syndrome, hereditary alpha tryptasemia, urticaria, Lyme disease, mast cell leukemia, chronic obstructive pulmonary disease, long COVID, asthma, inflammatory bowel disease, arthritis, allergy, and gout.” (Spec., p. 8). The specification does not provide detailed guidance regarding the use of the compounds of formula I to treat or prevent a flare to the genus of inflammatory conditions, of which the patient population is vast.
The existence of working examples relates to administering compounds BK40193, BK40195, BK40196 in vitro by contacting them with LUVA cells (immortal cell line that are maintained without stem cell factor (SCF) (Spec., p. 50, Example 2); administering compounds BK40193, BK40195, BK40196, and BK40197 intraperitoneally (I.P.) to 12-month old transgenic APP mice (Spec., pp. 52-54, Examples 5-8); and administering compounds BK40193, BK40195, BK40196, and BK40197 to wild type C57BL/6J mice treated with Compound 48/80, an inducer of mast cell activation (Spec., p.57, Example 10). The present disclosure does not provide working examples for methods of using the compounds of formula I in subjects having inflammatory conditions unrelated to mast cell activation, like RA.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each specific disease or disorder encompassed by the claims. As claimed, the indefinite scope of such diseases is essentially unbound.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. The breadth of the claims is broad in scope; the nature of the invention is sophisticated; state of the prior art is complex in relation to inflammatory conditions and is ascending towards the possibility of c-kit inhibitors possessing antirheumatic activity; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is limited to evaluation of compounds of formula I as claimed for reducing accumulation of mature mast cell; and does not demonstrate possession of a method of treating or preventing a flare in all inflammatory conditions within the scope of, “A method of treating an inflammatory condition or preventing a flare in the inflammatory condition in a subject in need thereof”; and the quantify of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Examiner recommends amending the claim to recite the specific inflammatory conditions relating to mast cells, e.g., in claims 24-26 that are supported by the disclosure.
(ii) Claims 28-29 are rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claims contain subject matter that was not described in the Specification in such a way as to reasonably convey to one of ordinary skill in the art that Applicant, at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), the Federal Circuit stated “the hallmark of written description is disclosure.” A specification adequately describes an invention when it “reasonably conveys to those skilled in the art the inventor had possession of the claimed subject matter as of the filing date.” Id. “A ‘mere wish or plan’ for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.” Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). In Ariad, the Federal Circuit explained what is required to meet the written description requirement:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357–58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1359.
Further, the written description of a genus, such as a chemical genus, “requires a precise structure, formula, [or] chemical name” of the claimed subject matter sufficient to distinguish it from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed. Cir. 1997). The Federal Circuit commented on that case in the Ariad decision:
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 (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.
The factors outlined in the above Federal Circuit cases are analyzed with respect to the claimed invention in turn below.
(A) The nature and scope of the claim invention in view of the specification: the claimed invention relates generally to the chemical art and more specifically to a method of treating an inflammatory condition or preventing a flare in the inflammatory condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the structure of Formula I, wherein the method further comprises administering a second therapeutic agent from the group consisting of non-steroidal anti-inflammatory agents, steroids, bronchodilators, and biologics. The claimed phrases “second therapeutic agent” and “non-steroidal anti-inflammatory agents, steroids, bronchodilators, and biologics” encompasses genera having millions of distinct embodiments.
The Specification does not provide any working examples for the claimed invention. The Specification generally mentions the compounds of Formula I are administered with a second therapeutic agent wherein the second therapeutic agent may be selected from non-steroidal anti-inflammatory agents, steroids, bronchodilators, biologic agents, and another c-kit inhibitor. Also, the Specification mentions the second therapeutic agent may be administered before, concurrent with, or after the administration of compounds of Formula I (Spec., p. 43, lines 23-28). The Specification does not provide any details related to a specific second therapeutic agent, other than specific c-kit inhibitors, nor does it provide any details related to a composition, a formulation, or a dose of a specific second therapeutic agent. The Specification does not provide any details related to administering a second therapeutic agent. The Specification does not provide any details related to testing the administration of compounds of Formula I and a second therapeutic agent for efficacy or synergy.
(B) The extent and content of the prior art: The compounds of Formula I are c-kit inhibitors (Spec., p. 2, lines 3-5). According to a review article, a combination of dasatinib (BCR-ABL and SRC family kinase inhibitor), midostaurine (FLT3 and c-kit inhibitor) or cladribine yielded synergistic effects in HMC-1.2 mast cells carrying the D816V c-KIT mutation. Another study employing antisense mcl-1 oligonucleotides in combination with midostaurine similarly showed a synergistic growth inhibition in the same cell line (Jensen et al., British Journal of Pharmacology (2008) 154, 1572–1582).
With respect to the claimed compounds, WO2020106825 describes a method of administering compounds of Formula I, like Compounds 1 and 2, and a second therapeutic agent to subjects having neurodegenerative disease, myodegenerative disease, prion disease, or lysosomal storage disease (LSD).
The second therapeutic agents disclosed for neurodegenerative, myodegenerative, or prion disease include agents like a dopamine agonist, an anticholinergic agent, a cholinergic agent, tyrosine kinase inhibitors, etc. and can be administered to a subject prior to, simultaneously with, or subsequent to administration of the compounds having Formula I.
The second therapeutic agents disclosed for LSD include agents like an enzyme, hematopoietic stem cells, a bone marrow transplant, gene therapy, or a small molecule. Specific examples include administration of a recombinant enzyme like imiglucerase or a small molecule inhibitor miglustat for Type I Gaucher disease (Id., Abstract, pp. 19-20, 27). However, no specific examples of administration of a second therapeutic agent are disclosed.
Accordingly, while the prior art does describe a combination therapy of the c-kit inhibitor midostaurine and a gene therapy with an antisense mcl-1 oligonucletide and the BCR-ABL inhibitor dasatinib, the prior art does not describe examples of administering c-kit inhibitors compounds of Formula I and a second therapeutic agent selected from the group consisting of non-steroidal anti-inflammatory agents, steroids, bronchodilators, and a biologic.
(C) The maturity of the science or technology: while combination drug therapies exist for administration of c-kit inhibitors along with a second therapeutic agent, the claims are directed to administration of compounds of Formula I and a second therapeutic agent. There does not appear to be any pre-clinical or clinical trials that provide a proof of concept for the claimed invention to a method of administering compounds of Formula I and a second therapeutic agent selected from the group consisting of non-steroidal anti-inflammatory agents, steroids, bronchodilators, and a biologic. As such, the science relevant to the claimed invention is in its infancy.
(D) The predictability of the aspect at issue: the pharmaceutical art is generally recognized as unpredictable. In re Fisher, 427 F.2d 833, 839 (CCPA 1970). The art requires each potential drug candidate to be assessed for physiological activity. Id. The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement.
When the above factors and evidence discussed therein are considered as a whole, the specification (in view of the prior art) does not adequately describe a representative number of species to support the claimed genera of administering c-kit inhibitor compounds of Formula I and a second therapeutic agent selected from the group consisting of non-steroidal anti-inflammatory agents, steroids, bronchodilators, and a biologic. Accordingly, the Specification does not reasonably convey to those skilled in the art the Applicant had possession of the claimed subject matter as of the filing date.
Examiner recommends canceling claims 28-29.
Claim Rejections - 35 USC § 112 (b)
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 24-25 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “related to” in claims 24-25 is a relative term which renders the claim indefinite. The term “related to” 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.
For instance, claim 24 recites: “The method of claim 1, wherein the inflammatory condition is related to c-kit upregulation or hyperactivity.” Giving the claim its BRI, the inflammatory condition, as instantly claimed, is not solely limited to an inflammatory condition affected by c-kit upregulation or hyperactivity. It can be reasonably interpreted as including other targets that may contribute to said inflammatory condition, like overactive PDGFR in synoviocytes of RA subjects (Juurikivi et al., p. 1131). The same ambiguity exists in claim 25, because the inflammatory condition “related to an overabundance of mast cells” does not exclude other factors contributing to said inflammatory condition. Moreover, it is unclear if c-kit upregulation or hyperactivity and an overabundance of mast cells are the main targets of the treatment of the inflammatory condition or indirect contributors.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
Claims 1-27 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020106825 (“Wolf”) in view of El-Agamy et al., European Journal of Pharmacology, 690 (2012) 1–3 (“El-Agamy”).
Wolf teaches compounds of Formula I, namely, BK40197, BK40143, BK40195, and BK40196 (pp. 36-38), which can be administered locally (p. 32) or systemically (p. 32, claim 14). Wolf also teaches the compounds of Formula I can inhibit one or more receptor tyrosine kinases selected from DDR1, DDR2, cKIT, etc. (p. 24).
Wolf does not teach administering compounds BK40197, BK40143, BK40195, and BK40196 to subjects having an inflammatory condition associated with c-kit upregulation or hyperactivity leading to an overabundance of mast cells.
El-Agamy teaches mast cells have been widely associated with allergic reactions and parasite infections, but recent studies have highlighted the important role of these cells in chronic inflammatory diseases. Inappropriate c-kit activation causes accumulation of mast cells in tissues resulting in mastocytosis (p. 1, Abstract). El-Agamy also teaches mast cell activation is characterized by accumulation of pathological mast cells in potentially any or all organs and tissues. “The percentage of human mast cells in bronchoalveolar fluid from patients with sarcoidosis or interstitial fibrosis is greater than in bronchoalveolar fluid from healthy individuals and patients with idiopathic interstitial pulmonary fibrosis show evidence of mast cell degranulation and elevated mast cell numbers. Recent reports have shown that c-kit sustains and/or maintains normal alveolar architecture in the lungs of mice” (p. 2, 1st column). Mast cells express in their membrane c-kit which has an extracellular domain that binds to stem cell factor (SCF) (p. 2, 1st column). Sunitinib, a c-kit inhibitor, has been shown to inhibit c-kit activity in systemic mastocytosis, and is considered to have the potential to inhibit mast cell functions and allergic responses through blunting of the c-kit activity essential for the survival, differentiation, and other functions of mast cells. El-Agamy concludes by stating the beneficial role of c-kit inhibitors on different mast cell associated diseases. (p. 2, 2nd column).
El-Agamy does not teach compounds having the structure of Formula I as instantly claimed.
Wolf and El-Agamy are analogous art because they are both in the field of analyzing small-molecule c-kit inhibitors. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art, to administer the c-kit inhibitors, locally or systemically, taught by Wolf to subjects possessing c-kit related mast cell disorders, like mastocytosis, as taught by El-Agamy to arrive at the claimed invention. The combination of these prior art elements would have yielded predictable results because Wolf teaches compounds BK40197, BK40143, BK40195, and BK40196 inhibit various receptor tyrosine kinases, including c-kit, and El-Agamy teaches c-kit inhibitors play a beneficial role on different mast cell associated diseases (MPEP §2143(A)). Furthermore, El-Agamy explicitly suggests c-kit inhibitors play a beneficial role on different mast cell associated diseases and that further studies should be conducted to investigate potential therapeutic effect of c-kit inhibitors in the management of such conditions. This suggestion would have led a PHOSITA to administer the compounds taught in Wolf to subjects having a mast cell disorder, like mastocytosis, with a reasonable expectation of success (MPEP §2144(G)).
Regarding claims 22 and 25, El-Agamy teaches mast cell activation is characterized by an accumulation of pathogenic mast cells in potentially any or all organs and tissues, and sunitinib, a c-kit inhibitor, has been shown to inhibit c-kit activity in systemic mastocytosis, and is considered to have the potential to inhibit mast cell functions and allergic responses through blunting of the c-kit activity essential for the survival, differentiation, and other functions of mast cells (vide supra). Therefore, it would have been prima facie obvious to a PHOSITA to substitute a c-kit inhibitor like sunitinib, as taught by El-Agamy, for compounds BK40197, BK40143, BK40195, or BK40196 as taught by Wolf, because they are recognized equivalents for the same purpose, c-kit inhibition (MPEP §2144.06(II)). The administration of the compounds taught by Wolf would yield predictable results, namely, a decrease in the overabundance of mast cells thereby increasing the ratio of immature mast cells to mature mast cells.
Regarding claims 23-24, El-Agamy teaches imatinib administration decreases allergic peribronchial eosinophil accumulation, airway hyperreactivity, and cytokine levels in vivo. These effects have been attributed to imatinib’s ability to effectively block c-kit mediated mast cells degranulation, c-kit-induced cytokine release in mast cells and inhibition of SCF-dependent mast cell adhesion (p. 2, 2nd column). Substituting the compounds taught in Wolf for imatinib would have been prima facie obvious to a PHOSITA they are recognized equivalents for the same purpose, c-kit inhibition (MPEP §2144.06(II)).
Claims 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over WO2020106825 (“Wolf”) in view of El-Agamy et al., European Journal of Pharmacology, Volume 690, Issues 1–3, 2012, Pages 1-3, (“El-Agamy”), further in view of Alvarado et al., Allergy. 2022;77:2393–2403 (“Alvarado”) .
The teachings of Wolf and El-Agamy are discussed above and are incorporated by reference herein.
Regarding claims 28-29, Wolf and El-Agamy do not teach a method of administration of a compound of Formula I and a second therapeutic agent to a subject having an inflammatory condition.
Alvarado teaches administration of CDX-0159, an anti-KIT monoclonal antibody that potently suppresses mast cells (MCs) in human healthy volunteers (p. 2393, Background). CDX-0159 inhibits SCF-dependent KIT activation in vitro, and led to dose-dependent suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation (p. 2393, Conclusion).
Wolf, El-Agamy, and Alvarado are analogous art to the claimed invention because they are in the same field of analyzing agents for c-kit inhibition. Therefore, it would have been prima facie obvious to a PHOSITA to combine the teachings of Wolf, El-Agamy, and Alvarado and arrive at the methods instantly claimed. A PHOSITA would have been motivated to administer both, the c-kit inhibitor compounds taught by Wolf and the monoclonal antibody biologic taught by Alvarado, as a second composition, to subjects having mastocytosis, because El-Agamy teaches inappropriate c-kit activation causes accumulation of mast cells in tissues resulting in mastocytosis. The teachings of Wolf and Alvarado describe compositions known for the same purpose, c-kit inhibition (MPEP §2144.06(I)).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 12,246,009 (“ ’009 ”) in view of WO2020106825 (“Wolf”) in view of El-Agamy et al., European Journal of Pharmacology, Volume 690, Issues 1–3, 2012, Pages 1-3, (“El-Agamy”) further in view of Alvarado et al., Allergy. 2022;77:2393–2403 (“Alvarado”) .
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 1-29 are obvious over claims 1-28 of ‘009 in view of Wolf and El-Agamy.
At least claims 8-9 and 21-22 of ‘009 recite the structural limitation of the instant compound claims. Claim 7 of ‘009 recites methods of use of said compounds such as, methods of treating a neurodegenerative disease, a myodegenerative disease, a prion disease, or a lysosomal storage disease (LSD). Claim 27-28 of ‘009 discloses further administering a second therapeutic agent to a subject having LSD, wherein the second therapeutic agent can be enzyme replacement therapy, gene therapy, etc.
‘009 does not teach administering the compounds to inhibit c-kit nor does it teach administering the compounds to treat mast cell disorders.
Wolf teaches examples of compounds of Formula I, namely, BK40197, BK40143, BK40195, and BK40196 (pp. 36-38) and can be administered locally (p. 32) or systemically (p. 32, claim 14). Wolf also teaches the compounds of Formula I inhibit one or more receptor tyrosine kinases selected from DDR1, DDR2, cKIT, etc. (p. 24).
Wolf does not teach administering compounds BK40197, BK40143, BK40195, and BK40196 to subjects having an inflammatory condition associated with c-kit upregulation or hyperactivity leading to an overabundance of mast cells.
El-Agamy teaches mast cells have been widely associated with allergic reactions and parasite infections, but recent studies have highlighted the important role of these cells in chronic inflammatory diseases. Inappropriate c-kit activation causes accumulation of mast cells in tissues resulting in mastocytosis (p. 1, Abstract). El-Agamy also teaches mast cell activation is characterized by accumulation of pathological mast cells in potentially any or all organs and tissues. “The percentage of human mast cells in bronchoalveolar fluid from patients with sarcoidosis or interstitial fibrosis is greater than in bronchoalveolar fluid from healthy individuals and patients with idiopathic interstitial pulmonary fibrosis show evidence of mast cell degranulation and elevated mast cell numbers. Recent reports have shown that c-kit sustains and/or maintains normal alveolar architecture in the lungs of mice” (p. 2, 1st column). Mast cells express in their membrane c-kit which has an extracellular domain that binds to stem cell factor (SCF). SCF is the principal growth factor for mast cells and induces mast cell proliferation and suppresses mast cell apoptosis. SCF stimulates mast cell degranulation with release of mediators, such as histamine, and also expression of inflammatory cytokines and chemokines (p. 2, 1st column). Sunitinib, a c-kit inhibitor, has been shown to inhibit c-kit activity in systemic mastocytosis, and is considered to have the potential to inhibit mast cell functions and allergic responses through blunting of the c-kit activity essential for the survival, differentiation, and other functions of mast cells. El-Agamy concludes by stating the beneficial role of c-kit inhibitors on different mast cell associated diseases. (p. 2, 2nd column).
El-Agamy does not teach administration a second therapeutic, like a biologic, NSAID, steroids, or bronchodilators.
Alvarado teaches administration of CDX-0159, an anti-KIT monoclonal antibody that potently suppresses mast cells (MCs) in human healthy volunteers (p. 2393, Background). CDX-0159 inhibits SCF-dependent KIT activation in vitro, and led to dose-dependent suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation (p. 2393, Conclusion).
Regarding claims 1-27, claims 8-9 and 21-22 of ‘009 recites compounds mimetic of compounds in instant claim 16 and 19, and methods of treating a neurodegenerative disease, a myodegenerative disease, a prion disease, or a lysosomal storage disease (LSD). Wolf teaches c-kit inhibitors BK40197 and BK40143. El-Agamy teaches inappropriate c-kit activation causes accumulation of mast cells in tissues resulting in mastocytosis. El-Agamy also teaches mast cell activation is characterized by accumulation of pathological mast cells in potentially any or all organs and tissues. It would have been prima facie obvious to a PHOSITA to administer the compounds recited in ‘009, imitative of compounds BK40197 and BK40143 which are c-kit inhibitors as taught by Wolf, to treat mast cell disorders induced by high levels of c-kit activation as taught by El-Agamy to arrive at the method instantly claimed.
Regarding claims 28-29, Alvarado teaches administration of CDX-0159 to suppress MC accumulation. It would have been prima facie obvious to a PHOSITA to administer both the compounds recited in ‘009, imitative of compounds BK40197 and BK40143 which are c-kit inhibitors as taught by Wolf, and a biologic as taught by Alvarado to treat mast cell disorders induced by high levels of c-kit activation as taught by El-Agamy to arrive at the method instantly claimed. The teachings of Wolf and Alvarado describe compositions known for the same purpose, c-kit inhibition (MPEP §2144.06(I)).
Conclusion
No claims are allowed.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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