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
Claims 1-16 are pending. Claims 3-6 and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species. Therefore, Claims 1, 2, 7-10, and 12-16 are under examination.
Election/Restrictions
Applicant's election with traverse of pulmonary fibrosis as the fibrotic disease that is a CRAC channel-related and/or DDR2-related disorder/condition and atovaquone as the at least one ingredient, in the reply filed on 12/22/2025 and 4/13/2026 is acknowledged. The traversal is on the ground(s) that there is no search burden. This is not found persuasive because a search burden exists if it would require multiple search queries to find art in order to address each species claimed.
The requirement is still deemed proper and is therefore made FINAL.
Claims 3-6 and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the replied filed on 12/22/2025 and 4/13/2026.
Priority
This application is a continuation application of PCT Application No. PCT/CN2024/073037, filed on January 18th, 2024, which claims the benefit of U.S. Provisional Application No. 63/480,626, filed on January 19th, 2023.
Information Disclosure Statement
The Information Disclosure Statements filed 07/1/2025 and 03/25/2026 have been considered by the Examiner. The submissions are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code - see “http://rsbweb.nih.gov/ij/” at 0094 at p. 21. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 1, 7, 9, 13, and 16 are objected to because of the following informalities:
Claim 1:
Line 2: because this is its first time appearing in the claims, the abbreviation DDR2 should be spelled out completely;
Line 3: the term “administering a subject in need thereof with a pharmaceutical composition” should be changed to “administering to a subject in need thereof, a pharmaceutical composition”;
End of claim: the term “thereof” at the end of the claim should be deleted.
Claim 7:
Line 2: The term “the fibrotic disorder” should be changed to “a fibrotic disorder”;
Line 5: The terms “WRG-28 precursors” and “atovaquone precursors” should be singularized because “at least one” of the members of the Markush group may be administered.
Claim 9
Lines 2-3: “drug-induced fibrosis” appears in a list with “infection-induced fibrotic disorder,” “obstruction-induced fibrotic disorder,” and “inflammatory-induced fibrotic disorder.” For consistency, the term “drug-induced fibrosis” may be changed to “a drug-induced fibrotic disorder”;
Last line: the term “an” should be inserted in front of the term “inflammatory”.
Claim 13:
Line 1: the term “wherein” should be added after the text “claim 1,”;
Lines 1-2: The terms “WRG-28 precursors” and “atovaquone precursors” should be singularized because “at least one” of the members of the Markush group may be administered;
Line 2: the term “inhibit” should be “inhibits”.
Claim 16:
Lines 2-3: the term “in a cell of a subject, comprising administering the subject in need thereof with a pharmaceutical composition” should be changed to “in a cell of a subject in need thereof, comprising administering to the subject, a pharmaceutical composition”.
End of claim: the term “thereof” at the end of the claim should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 2, 7-10, and 12-16 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 pulmonary fibrosis, does not reasonably provide enablement for preventing pulmonary fibrosis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement requires a determination of whether the disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Claim 1 reads on:
“a method for treating or preventing pulmonary fibrosis, comprising administering atovaquone to a subject”
Thus, the claims are drawn to preventing pulmonary fibrosis from occurring in a subject by administration of atovaquone. This is despite 1) the lack of sufficient support for prevention of a single CRAC- or DDR2-related condition/disorder, less pulmonary fibrosis (PF) and 2) the lack of sufficient support for prevention of PF in the art.
The nature of the invention:
The invention relates to a method of treating or preventing a CRAC- or DDR2-related condition/disorder with atovaquone, WRG-28 or a precursor thereof. Prevention broadly includes not only therapeutic intervention, but also prophylaxis and inhibiting or stopping PF before it arises. The invention is based on inhibiting activation of CRAC/DDR2/SOCE and, thereby, treat or prevent a CRAC- or DDR2-related disorder/condition such as PF. The claims encompass preventing diseases that cannot be prevented including PF.
Breadth of claim:
The breadth of the claims is wide: it purports to cover the treatment and prevention of diseases that cannot be prevented. By contrast, the disclosure does not support the prevention of diseases such as those claimed.
State and predictability of the art:
The state of the art of PF therapy recognized that PF cannot be prevented. There are many causes of PF that are not preventable including
asbestos, metal dust or chemicals, and wearing a respirator (a mask that filters particles from the air) if you have to work with them
chronic allergic reactions, like hay, grain, bird droppings or feathers, and heating and cooling systems
One can reduce the risk of lung scarring from environmental exposures by avoiding these causes but PF is not preventable as claimed. See Cleveland Clinic, “Pulmonary Fibrosis.” May 5, 2025, https://my.clevelandclinic.org/health/diseases/10959-pulmonary-fibrosis.
Relative skill level:
One of ordinary skill in the art is one with access to reagents, tools and equipment used for diagnosing disease, performing tests and/or administering treatment to individuals. The skilled artisan also has many years of training and experience in either the clinical or laboratory environment or both. Therefore, it is clear that the level of skill of one in the art is high. However, this high level of skill is overcome in view of the limited teachings provided by the specification and the unpredictable state of the art, it would require the skilled artisan undue experimentation to make and use the invention commensurate to the scope of the claims.
The amount of direction or guidance provided and the presence or absence of working examples:
Although the specification includes several working examples involving induced fibrosis models, pulmonary fibroblast assays, and bleomycin-induced PF in mice, the examples are limited to specific experimental systems and conditions. The specification does not provide sufficient guidance regarding which PF etiologies, disease stages, patient populations, dosing regimens, treatment windows, or predictive biomarkers would allow reliable prevention of PF across the full scope of the claims. Furthermore, the working examples primarily demonstrate reduction of fibrosis-associated markers, fibrosis severity or progression in induced experimental models rather than true prevention of PF generally. A person of ordinary skill in the art (POSA) would therefore be required to engage in substantial undue experimentation to determine whether the claimed composition can prevent PF. Thus, the specification fails to provide any substantive guidance to prevent the claimed diseases.
The quantity of experimentation necessary:
Because of the known unpredictability of the art, and in the absence of sufficient experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used for prevent the claimed diseases as inferred by the claim and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 16 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dearn, Alan Roy (US 6,649,659 B1).
Claimed invention
Claim 16 is drawn to a method for inhibiting CRAC and/or DDR2 activation in a cell of a subject, comprising administering a pharmaceutical composition comprising an effective amount of atovaquone and pharmaceutically acceptable carriers thereof.
Prior art
Dearn teaches atovaquone pharmaceutical compositions for use in a method for the treatment and/or prophylaxis of protozoal infections in mammals which comprises administering to said mammals an effective amount of particles of atovaquone and one or more pharmaceutically acceptable carrier. (Dearn, Claim 11.)
Dearn therefore, discloses each active step and component recited in the claim – “administering to a subject an effective amount of atovaquone and pharmaceutically acceptable carriers” – which would meet the biological result or mechanism achieved by administering the same compound/composition administered in the same manner to a subject. Properties/results inherent to administering atovaquone does not render the claimed method novel.
Claim 16 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gupta et al. (Int J Mol Sci. 2021 May 13; 22(10): 5150. doi: 10.3390/ijms22105150 – submitted with IDS).
Claimed invention
Claim 16 is drawn to a method for inhibiting CRAC and/or DDR2 activation in a cell of a subject, comprising administering a pharmaceutical composition comprising an effective amount of atovaquone and pharmaceutically acceptable carriers thereof.
Prior art
Gupta teaches that atovaquone is a pharmaceutical compound having therapeutic activity by suppressing immunosuppressive mediators, including TGFbeta. In particular, Gupta teaches that the effect of atovaquone in different breast tumor models, including oral gavage in mice, showed that atovaquone significantly inhibited tumor growth by suppressing MDSCs and Tregs in blood and tumor cells, with a reduction in immunosuppressive cytokines including TGFbeta, IL-10 and RPS19. (Gupta, abstract, p. 3.)
Gupta therefore, discloses each active step and component recited in the claim – “administering to a subject an effective amount of atovaquone and pharmaceutically acceptable carriers” – which would meet the biological result or mechanism achieved by administering the same compound/composition administered in the same manner to a subject. Properties/results inherent to administering atovaquone does not render the claimed method novel.
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.
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.
Claims 1, 2, 7-10, and 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Min et al. (WO 02/085300 A2) in view of Gupta et al. (Int J Mol Sci. 2021 May 13;22(10):5150. doi: 10.3390/ijms22105150 – submitted with IDS).
Claimed invention
Claim 1 is drawn to a method for treating or preventing pulmonary fibrosis, comprising administering atovaquone to a subject.
Prior art
Min teaches pulmonary fibrosis (PF) can be treated with an inhibitor of TGFbeta, which plays a pivotal role in PF. (Min, title, abstract, p. 2, and claims 12 and 21.)
Min does not teach atovaquone.
However, atovaquone is a known TGFbeta inhibitor with pharmaceutical use for treating a subject with a disease by way of inhibiting TGFbeta. For example, Gupta teaches that atovaquone is a pharmaceutical compound having therapeutic activity by suppressing immunosuppressive mediators, including TGFbeta. In particular, Gupta teaches that the effect of atovaquone in different breast tumor models showed that atovaquone significantly inhibited tumor growth by suppressing MDSCs and Tregs in blood and tumor cells, with a reduction in immunosuppressive cytokines including TGFbeta, IL-10 and RPS19. (Gupta, abstract, p. 3.)
A person of ordinary skill in the art (POSA) would have found it obvious to treat PF with atovaquone because Min teaches that inhibition of TGFbeta is useful for treating PF, and Gupta teaches that atovaquone suppresses TGFbeta in vivo and has pharmaceutical therapeutic activity. Thus, a POSA would have sought to use atovaquone as the TGFbeta-suppressing agent of Gupta in the method of treating PF taught by Min, with a reasonable expectation of success, because both references identify TGFbeta suppression as a biologically relevant therapeutic mechanism.
Claims 2, 7-10, 12-16 (functions that result from administration of effective amounts of atovaquone to PF patients)
Claim 2 and Claim 7 limit the invention, wherein the CRAC channel-related disorder or condition and/or the DDR2-related disorder or condition is selected from the group that includes a fibrotic disorder. Claims 8-10 and 12 limit the invention, wherein the CRAC channel-related disorder or condition and/or the DDR2-related disorder or condition is a fibrotic disorder including an infection-induced fibrotic disorder, an obstruction-induced fibrotic disorder, drug-induced fibrosis, or inflammatory-induced fibrotic disorder (Claim 9) such as pulmonary fibrosis (Claim 8), thereby improving a pulmonary function and/or a TGFbeta-associated fibroblast activation (Claim 10), and wherein the TGFbeta-associated fibroblast activation is a TGFbeta1-associated fibroblast activation (Claim 12). Claim 13-15 limits the invention, wherein the atovaquone inhibits CRAC channel activation, DDR2 activation, store-operated Ca2+ entry (Claim 13), and/or cytokine expression such as IL-6 (Claims 14 and 15). As outlined above, Min teaches pulmonary fibrosis (PF) can be treated with an inhibitor of TGFbeta. With regard to the recitation of “improving a pulmonary function and/or a TGFbeta-associated fibroblast activation, wherein the TGFbeta-associated fibroblast activation is a TGFbeta1-associated fibroblast activation” or “atovaquone inhibiting IL-6”, upon the administration of the atovaquone as the TGFbeta inhibitor to the PF subject, these results would intrinsically occur as a function of the administered inhibitor. Thereby, the claimed results do not distinguish the claims over the prior art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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