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 .
DETAILED ACTION
This Office Action is responsive to the Response to Election/Restriction filed 11/12/2025. The preliminary amendment filed 09/11/2023 amended claims 1, 21, 22, 24, 30, 32, 34, and 37, and cancelled claims 8-9, 11, 14-20, 23, 27-29, 31, 33 and 35-36.
Claims 1-7, 10, 12-13, 21-22, 24-26, 30, 32, 34, and 37-38 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant’s election without traverse of a) Sedaghatian-type Spondylometaphyseal Dysplasia as the disease/disorder/condition mediated by GPX4, and b) azelnidipine as the compound, in the reply filed on 11/12/2025, is acknowledged.
Claims 4-5, 10, 12-13, 21-22, 24-26, 30, 32, 34, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
Claims 1-3, 6-7, and 38 are pending and examined on the merits herein.
Claim Objections
Claim 38 is objected to because of the following informalities:
In claim 38, line 3, the phrase of “a compound of Table 1A or 1B” should be replaced with the names and/or structures of the compound. Applicant is reminded that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. MPEP 2173.05(s)
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
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 1-3, 6-7, and 38 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 a method of inhibiting ferrostatin-1 with compound Nos. 1-110 as depicted in Tables 1A and 1B in patients with Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD), does not reasonably provide enablement for a method for treating a disease, disorder, or condition mediated by GPX4 in a patient by administering a compound selected from the group consisting of
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. 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 criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
Instant independent claim 1 recites:
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The claim is directed toward any disease, disorder or condition mediated by GPX4, and any compounds have has the following activity:
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Independent claim 38 is directed toward a method for treating a disease, disorder, or condition mediated by GPX4 comprising administering an effective amount of a compound of Table 1A or 1B or a pharmaceutically acceptable salt thereof.
The claim is directed toward any disease, disorder or condition mediated by GPX4, and any one of the 110 compounds or salts thereof in Tables 1A and 1B.
Thus, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a clinician or a scientist with a PhD.
State of the Prior Art
US 2006/0009502 to Horiuchi (published 2006, PTO-892) teaches a method for the prevention and/or treatment of hypertension by administering to a mammal, an angiotensin II receptor antagonist and the calcium channel blocker, azelnidipine (pgs. 12-13, claims 59, 61-62, 64). As evidenced by Zhang (GPX4, ferroptosis, and diseases, Biomedicine & Pharmacotherapy, published 2024, PTO-892), hypertension is a GPX4 mediated disease (3.4.2, beginning on pg. 8; 3 beginning on pg. 2).
US2017/0312260 to Chen (published 2017, PTO-892) teaches a method of treating cancer comprising administering a composition comprising azelnidipine (pgs. 5-6, claims 1-8).
As evidenced by Zhang, cancer is a GPX4 mediated disease (3.5. beginning on pg. 9).
US 2023/0167058 to Stockwell teaches a method for treating or ameliorating the effects of a GPX4-associated disease, modulating the activity of GPX4, increasing the level of peroxide, or treating or ameliorating the effects of a cancer by administering to subjects a compound of
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(pgs. 48-53, claims 2, 7, 8-11, 49).
The compounds are taught as inducing ferroptosis (([0019]; [0025]; [0065]; [0079]; pgs. 49, 53, claims 7, 49). As evidenced by Gao, ferroptosis is an autophagic cell death process. As such, the compounds of Stockwell are autophagy activators as recited in instant claim 1.
Zhang teaches that GPX4 serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing a significant role in maintaining the redox homeostasis within the body. Together, GPX4 and ferroptosis contribute to the pathophysiology of several diseases (abstract). GPX4 exists in three physiological isoforms, each exhibiting distinct spatiotemporal expression patterns during embryonic development and in adulthood. Each isoform has different functions (pg. 1). GPX4 is linked to many diseases such as sepsis; sepsis-induced acute lung injury, kidney injury, cardiac dysfunction, encephalopathy, liver injury; nervous system diseases such as neurodegenerative diseases, stroke, neuropathic pain; ischemia reperfusion injury; cardiovascular disease such as atherosclerosis, hypertension, cardiomyopathy, cardiac hypertrophy; and cancer (pg. 3-10).
Thus, the prior art teaches that numerous, un-related disease are affected by GPX4 and that such diseases are treated by specific compounds, which are structurally and functionally distinct.
Predictability in the Art
Zang teaches that despite the significant role of GPX4 in ferroptosis, research into its regulation at transcriptional, translational, and post-translation activity levels under physiological and pathological conditions remains sparse. Studies have shown that GPX4 expression is influenced by a multitude of regulatory mechanisms (pg. 10, “4.”). Zang teaches that although the specific mechanisms are not thoroughly explored, the regulatory mechanisms of GPX4 possess substantial research potential, and applications for diseases might offer vast investigative prospects. Zang further teaches that as a key target in the treatment of numerous diseases associated with ferroptosis, various modulators of GPX4 have been developed and studied. However, the in vivo application of GPX4 inhibitors currently remains pessimistic, especially due to the risk of excessive systemic toxicity caused by non-selective inhibition. Clinical applications of GPX4 inhibitors are yet to be reported, with many studies still in experimental stages (pg. 11, Cols. 1-2).
In summary, Zang states that “targeted research on GPX4 holds broad prospects, yet clinical applications may still be some distance away. . .given the crucial role of GPX4 in cell survival and homeostasis, as well as its involvement in numerous physiological and pathological processes, targeted drugs for GPX4 could potentially engender adverse side effects. Consequently, despite in-depth exploration into GPX4, there remains a multitude of enigmatic domains awaiting discovery, and the current foundational research might be overly simplistic for direct transition into clinical practice” (pg. 11, Cols. 2).
In view of the above teachings by Zang and the teachings of the prior art, the art of treating GPX4 diseases, disorders, and conditions is unpredictable.
Working Examples
The instant example shows the effects of compounds tested on three cell lines, RAG01 which are fibroblasts of a patient diagnosed with Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD); RAG02 which are fibroblasts of a SSMD patient’s father; and GM09503 which are cells derived from a healthy donor ([0172]). The cells are incubated with compounds from instant Table 1A and 1B. A 0.1% dimethylsulfoxide was used as a vehicle control and a 1uM ferrostatin-I was used as a control, wherein ferrostatin-I inhibits ferroptosis ([0172]). The EC50 value for the activity of ferrostatin-1 for RAG01 cells, i.e., the inhibition of ferroptosis, was determined for the 110 compounds in instant Tables 1A and 1B, wherein the EC50 values varied from 0.077 (Ex. No. 72) to 6.814 (Ex. No. 22).
Direction and Guidance
In view of the single, ex-vivo example and the unpredictability of the art of treating GPX4 diseases, disorders, or conditions, the instant specification does not provide sufficient direction or guidance to use the invention as instantly claimed.
Moreover, the 110 compounds do not share a common core structure (see pgs. 22-43 of the instant specification), making it impossible to determine a structure-function relationship between the compounds and their ability to inhibit ferrostatin-1.
Quantity of Experimentation
The amount of experimentation required to determine which GPX4 diseases, disorders, or conditions are treated by which of the following classes of compounds:
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, would be astronomical. This amount of experimentation amounts to invention, not development; it is an undue amount of experimentation.
Thus, while being enabling for a method of inhibiting ferrostatin-1 with compound Nos. 1-110 as depicted in Tables 1A and 1B in patients with Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD), the instant specification does not reasonably provide enablement for a method for treating a disease, disorder, or condition mediated by GPX4 in a patient by administering a compound selected from the group consisting of
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Claim Rejections - 35 USC § 102
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 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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 6, and 38 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 2006/0009502 to Horiuchi (published 2006, PTO-892), as evidenced by Zhang (GPX4, ferroptosis, and diseases, Biomedicine & Pharmacotherapy, published 2024, PTO-892).
Regarding claims 1 and 38, Horiuchi teaches a method for the prevention and/or treatment of hypertension by administering to a mammal, an angiotensin II receptor antagonist and the calcium channel blocker, azelnidipine (pgs. 12-13, claims 59, 61-62, 64).
Horiuchi teaches the mammal as a human (pgs. 12-13, claim 60, 65).
As evidenced by Zhang, hypertension is a GPX4 mediated disease (3.4.2, beginning on pg. 8; 3 beginning on pg. 2).
Regarding claim 2, Horiuchi teaches azelnidipine as a 1,4-dihydropyridine compound that is a calcium channel blocker (pg. 13, claim 64).
Regarding claim 3, Horiuchi teaches azelnidipine.
Regarding claim 6, [0156] of the instant specification teaches GPX4 deficiency as associated with ferroptosis. As evidenced by Zhang, hypertension is characterized by high levels of ferroptosis (pg. 8, 3.4.2.). As such, hypertension is a disease/disorder/condition associated with a deficiency in GPX4.
Claims 1-3 and 38 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US2017/0312260 to Chen (published 2017, PTO-892), as evidenced by Zhang (GPX4, ferroptosis, and diseases, Biomedicine & Pharmacotherapy, published 2024, PTO-892).
Regarding claims 1 and 38, Chen teaches a method of treating cancer comprising administering a composition to a subject comprising azelnidipine (pgs. 5-6, claims 1-8).
As evidenced by Zhang, cancer is a GPX4 mediated disease (3.5. beginning on pg. 9).
Though Chen does not explicitly teach the subject as a human, the cancers taught by Chen are human cancers, and in [0005] Chen teaches cancer patients in the world, and in [0021] Chen specifically teaches human cell lines. As such, it is reasonable to assume that the subject taught by Chen is human.
Regarding claim 2, as evidenced by [0043] of the Specification, azelnidipine is a dihydropyridine calcium channel blocker.
Regarding claim 3, Chen teaches azelnidipine.
Claims 1 and 6 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0167058 to Stockwell (effectively filed 03/13/2020, PTO-892), as evidenced by Gao (Ferroptosis is an autophagic cell death process, Cell Research, published 2016, PTO-892) and Zhang (GPX4, ferroptosis, and diseases, Biomedicine & Pharmacotherapy, published 2024, PTO-892).
Regarding claim 1, Stockwell teaches a method for treating or ameliorating the effects of a GPX4-associated disease, modulating the activity of GPX4, increasing the level of peroxide, or treating or ameliorating the effects of a cancer by administering to subjects a compound pgs. 48-53, claims 2, 7, 8-11, 49).
Stockwell teaches humans as subjects ([0084]).
The compounds are taught as inducing ferroptosis (([0019]; [0025]; [0065]; [0079]; pgs. 49, 53, claims 7, 49). As evidenced by Gao, ferroptosis is an autophagic cell death process. As such, the compounds of Stockwell are autophagy activators as recited in instant claim 1.
Regarding claim 6, Stockwell teaches its methods for the treatment of neurodegenerative disorders (pg. 51, claim 8). As evidenced by Zhang, neurodegenerative disorders are characterized by the loss or mutation of GPX4 (pgs. 5 and 7, 3.2.1.). As such, neurodegenerative disorders are a disease/disorder/condition associated with a deficiency in GPX4.
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 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.
Claims 1, and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0167058 to Stockwell (effectively filed 03/13/2020, PTO-892), as evidenced by Gao (Ferroptosis is an autophagic cell death process, Cell Research, published 2016, PTO-892), and Zhang (GPX4, ferroptosis, and diseases, Biomedicine & Pharmacotherapy, published 2024, PTO-892).
Stockwell is applied to claims 1 and 6 as discussed above and incorporated herein.
Stockwell additionally teaches spondylometaphyseal dysplasia as a GPX4-associated disease (pg. 51, claim 8), and specifically exemplifies Sedaghatian type spondylometaphyseal dysplasia ([0159]).
While Stockwell teaches a method of treating spondylometaphyseal dysplasia by administering to subjects compounds that induce ferroptosis, it differs from that of instant claim 7 in that it does not teach Sedaghatian type spondylometaphyseal dysplasia.
As such, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select Sedaghatian type spondylometaphyseal dysplasia as the spondylometaphyseal dysplasia, to arrive at instant claim 7. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success because Stockwell teaches treating spondylometaphyseal dysplasia, and specifically exemplifies studying the GPX4 mutation in patients with Sedaghatian type spondylometaphyseal dysplasia.
As such, an ordinary skilled artisan would have reasonably expected the methods of Stockwell to treat Sedaghatian type spondylometaphyseal dysplasia.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 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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/LAUREN WELLS/Examiner, Art Unit 1622