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
The status of the claims are as follows:
Claims 1-20 are pending.
Claims 6, 12, and 18 are withdrawn.
Claims 1-5, 7-11, 13-17, and 19-20 are rejected.
Election/Restrictions
It is acknowledged that Applicant’s correction of the typographical error in the Restriction Requirement, filed on 06/11/2026, is correct. Applicant’s election without traverse of Group I, drawn to claims 1-5, 7-11, 13-17, and 19-20 in the reply filed on 08/11/2026 is acknowledged.
Claims 6, 12, and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/11/2026.
Priority
Acknowledgement is made that Instant Application 18/740,951, filed on 06/12/2024 claims foreign priority to CN202410053142.8, filed on 01/12/2024. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
Applicant has elected to not provide an information disclosure statement for this invention.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-3, 7-9, 13-15, and 19-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ishikawa (US 9,604,988 B2, published 03/28/2017) in view of Murphy (WO 2021/252650 A1, published 12/16/2021), as motivated by Ernst (Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response. J. Exp. Med. 2002, 196(5), 589-604. Doi: 10.1084/jem.20020873), and motivated by Poh (Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression. Cancer Cell., 2017, 31(4), 563-575. Doi:10.1016/j.ccell.2017.03.006) and motivated by Zhang (Enhanced IL-1 Beta and Tumor Necrosis Factor-Alpha Release and Messenger RNA Expression in Macrophages from Idiopathic Pulmonary Fibrosis or After Asbestos Exposure. J. Immunol. 1993, 150, 4188-4196. PMID: 8473757).
Claim 1 is directed to a method for preparation of a drug for treating pulmonary fibrosis using a hematopoietic cell kinase (HCK) inhibitor.
Ishikawa teaches methods for treating acute myeloid leukemia and inhibiting growth of leukemia stem cells comprising administering to a patient a compound with HCK inhibition (column 2, liens 15-25). Specifically, Ishikawa teaches Example 1 (hereafter referred to as RK-20449) (column 21, lines 25-50), with an HCK inhibition IC50 of 1.1 nM (column 23, line 21)
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The difference between the teaching of Ishikawa and the Instant Application is that Ishikawa fails to teach the use of HCK inhibitor RK-20449 as a treatment option for pulmonary fibrosis.
However, Murphy teaches HCK inhibitors exhibit anti-fibrotic and anti-proliferative effects and are useful therapeutic agents for a variety of disorders, including lung fibrosis (page 1, paragraph 0003).
One of ordinary skill in the art would have been motivated to apply the compound of Ishikawa to treat the indications taught by Murphy because there is direct experimental evidence linking HCK inhibition to fibrotic therapy. For example, Ernst generated HCKF/F “knock-in” mice with a hypermorphic HCK “gain-of-function” mutation (page 599, right column, paragraph 2). Unlike their HCK–/ – “loss-of-function” counterparts, the “gain-of-function” mice spontaneously acquired a lung pathology consistent with pulmonary fibrosis, which together with inflammation, resulted in altered lung function and respiratory distress in aging mice (abstract). Further, Poh teaches HCKCA mice (mice expressing a constitutive active kinase encoded by a mutation in the endogenous HCK gene) had elevated levels of Il-1β and Tnf-α compared to wild type (page 30, Figure 4C). Poh further teaches the HCK inhibitor RK-20449 (IC50 1.1 nM, as taught by Ishikawa) reduced the expression level of both Il-1β and Tnf-α (page 33, Figure 6E). Lastly, Zhang teaches that Il-1β and Tnf-α are pro-inflammatory cytokines, both of which are elevated in idiopathic pulmonary fibrosis (page 4192, right column, paragraph 2; Figures 4-5).
Accordingly, one of ordinary skill in the art would have known that administering a composition comprising a potent HCK inhibitor such as RK-20449, as taught by Ishikawa, would have reduced levels of HCK products (e.g., Il-1β and Tnf-α), which are directly implicated in idiopathic pulmonary fibrosis, thereby ameliorating symptoms of pulmonary fibrosis, as taught by Murphy.
Claim 2 is directed to the method according to claim 1, wherein the HCK inhibitor is one or two selected from the group consisting of a modulator capable of reducing an HCK expression level and a modulator capable of reducing an HCK product.
The method taught by Murphy, comprising the HCK inhibitor of Ishikawa, would be capable of reducing HCK products (e.g., Il-1β and Tnf-α), as evidenced by Poh.
Claim 3 is directed to the method according to claim 2, wherein the modulator capable of reducing HCK expression level comprises RK-20449.
The combined teachings above establish a prima facie obvious case for ameliorating pulmonary fibrosis by administering an effective amount of the HCK inhibitor RK-20449.
The difference between the combined teachings and the Instant Application is that the combined fails to teach a method wherein the modulator is capable of reducing HCK expression level and comprises RK-20449.
Although the property of "reducing HCK expression level” is not explicitly described in the cited prior art, the Instant Specification states that RK-20449 inhibits the transcription level of HCK in mouse lung tissue (page 7, paragraph 0058; Fig. 1). Therefore, the property of the compound to reduce HCK expression level in a treated patient must necessarily be present in the prior art RK-20449 composition, because products of identical chemical composition cannot exert mutually exclusive properties when prepared or used in the same manner under the same circumstances. Furthermore, as stated in MPEP 2112.02, “[u]nder the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered anticipated by the prior art device.” Accordingly, a composition comprising RK-20449 would necessarily be capable of reducing HCK expression level.
Claims 7-9 are directed to the methods according to claims 1-3, respectively, wherein the drug ameliorates pulmonary dysfunction.
The method of Ishikawa in view of Murphy teaches RK-20449 can be used to ameliorate pulmonary dysfunction, wherein the dysfunction is pulmonary fibrosis.
Claims 13-15 are directed to the methods of claims 1-3, respectively, wherein the drug ameliorates pulmonary inflammation and pulmonary fibrosis.
The method of the above combined teachings shows RK-20449 can be used to ameliorate pulmonary fibrosis through reduction of HCK products, for example Il-1β and Tnf-α (see Poh). Both Il-1β and Tnf-α are pro-inflammatory cytokines which are elevated in idiopathic pulmonary fibrosis (see Zhang). Accordingly, reducing the expression level of pro-inflammatory cytokines would result in ameliorating pulmonary inflammation.
Claim 19 is directed to a drug for treating pulmonary fibrosis, comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient comprises the modulator RK-20449 that reduces the HCK expression level according to claim 3.
Ishikawa teaches pharmaceutical compositions comprising RK-20449 as an active ingredient (column 17, lines 14-16) and further comprising pharmaceutical carriers to humans and nonhuman animals (column 17, lines 54-56).
Claim 20 is directed to the drug according to claim 19, wherein a dosage form of the drug is selected from the group consisting of a capsule, a powder, a tablet, and a solution.
Ishikawa teaches RK-20449 can be administered in various dosage forms, including oral preparations, for example tablets, capsules, and powders, and parenteral preparations such as injection preparations (e.g., solutions) (column 17, lines 58-62).
Claim(s) 4-5, 10-11, and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ishikawa, in view of Murphy, as motivated by Ernst, and motivated by Poh, and motivated by Zhang, in further view of MedChemExpress (Data available at least on 02/03/2023 https://web.archive.org/web/20230203231317/https://www.medchemexpress.com/A-419259-trihydrochloride.html).
The teachings of Ishikawa in view of Murphy as evidenced by Ernst, Poh, and Zhang are discussed above and incorporated herein by reference.
Claims 4 and 5 are directed to the method according to claim 3, wherein an RK-20449 solution has a concentration of 5 mg/mL to 15 mg/mL and the solvent is PBS.
Ishikawa further teaches it is generally adequate for an adult to take 1 to 50 mg of RK-20449 per day, by means of IV injection, IV drip infusion, subcutaneous injection, or IM injection, with the dosage varying depending on, for example, age, body weight, and severity of symptoms of the patient (column 18, lines 56-62). Furthermore, a vial or another container may be filled with an injection preparation, the resultant may be frozen, moisture may be removed via a conventional lyophilization technique, and a solution may then be prepared from the lyophilization product immediately before use, where other agents may be added, for example an isotonizing agent, as needed (paragraph 18, lines 34-39).
The difference between the combined teachings and the Instant Application is that the combined teachings fail to teach that the isotonizing agent is specifically PBS, and wherein the concentration of RK-20449 in solution is 5 to 15 mg/mL.
However, MedChemExpress teaches that RK-20449 trihydrochloride (A419259 trihydrochloride) is soluble in PBS at 100 mg/mL (168.92 nM) following ultrasonication (Solvent & Solubility; In Vivo).
One of ordinary skill in the art would have found it obvious to apply the teachings of MedChemExpress to know that common salt forms of RK-20449 can make PBS solutions up to 100 mg/mL. Therefore, said artisan could have arrived at the instantly claimed solution through routine optimization based on the needs of the patient.
Claims 10-11 are directed to the methods according to claims 4-5, respectively, wherein the drug ameliorates pulmonary dysfunction.
The method of the combined teachings above show RK-20449 can be used to ameliorate pulmonary dysfunction, wherein the dysfunction is pulmonary fibrosis.
Claims 16-17 are directed to the methods of claims 4-5, respectively, wherein the drug ameliorates pulmonary inflammation and pulmonary fibrosis.
The method of the above combined teachings show RK-20449 can be used to ameliorate pulmonary fibrosis through reduction of HCK products, for example Il-1β and Tnf-α (see Poh). Furthermore, both Il-1β and Tnf-α are pro-inflammatory cytokines which are elevated in idiopathic pulmonary fibrosis (see Zhang). Accordingly, reducing the expression level of pro-inflammatory cytokines would result in ameliorating pulmonary inflammation.
Conclusions
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Paul Arcoria whose telephone number is (571)272-8719. The examiner can normally be reached Mon-Fri 8:00-5:00 EST.
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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