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
The instant application is a 35 USC 371 National Stage filing of PCT/EP2022/051650, filed January 25, 2022, which claims priority under 35 USC 119(a)-(d) from European Application EP21305085.9, filed January 25, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) dated October 16, 2023 was in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS document was considered and signed copies of the 1449 forms are attached.
Election/Restrictions
Applicant’s election of the compound sibriline
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, in the reply filed December 19, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicant notes that claims 17-25, 27-30 and 33-36 read on the elected species.
In accordance with the MPEP, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species and the claims drawn to the elected species are allowable, the search of the Markush-type claim will be extended (see MPEP 803.02). If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
As indicated above, the Examiner searched the claimed invention based on the elected species above, wherein: the elected species was not found to be allowable over the prior art. Thus the scope of the search and examination was not expanded beyond the elected species of sibriline.
Status of Claims
Currently, claims 17-36 are pending in the instant application. Claims 26, 31-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention and/or species. Claims 17-25, 27-30 and 33-36 read on an elected species and are therefore under consideration in the instant application to the extent that they read on the elected embodiment.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 22-23 and 27-29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 22 recites the broad recitation “said aryl group being optionally substituted by…a halogen atom,…, and a (C1-C6 haloalkyl group),” and the claim also recites “in particular C(O)R59” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In addition to the abovementioned example, the rejected claims contain numerous instances of broad and narrow recitations within the same limitation, including R48 in claim 22, R55 to R65 in claim 22 (which set forth the broad recitation and then recite “notably” the more narrow recitation). Each instance of a broad recitation followed by “notably” or “in particular” or “such as” in the rejected claims is indefinite for the same reason as above. Appropriate correction is required.
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 18 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
- a method for inhibiting ferroptosis, or for
- a method for inhibiting ferroptosis in a patient having a disorder selected from those listed in claims 27-29,
does not reasonably provide enablement for
- preventing and/or treating any-and-all disorders associated with ferroptosis, including for example all those listed above.
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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include 1) the breadth of the claims, 2) the nature of the invention, 3) the state of the prior art, 4) the level of one of ordinary skill, 5) the level of predictability in the art, 6) the amount of direction provided by the inventor, 7) the existence of working examples, and 8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
[1] “Preventing” disorders:
Applicants are not enabled for preventing any of these disorders. The only established prophylactics are vaccines not the compounds such as presently used. In addition, it is presumed that “prevention” of the claimed disorders would require a method of identifying those individuals who will develop the claimed disorders before they exhibit the symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted
As discussed above, preventing diseases required identifying those patients who will acquire the disease before the disease occurs. This would require extensive and potentially open-ended clinical research on healthy subjects. For example, identification of individuals who will acquire such generic disorders as the “traumatic brain injury” and “chronic infections” is not currently supported by the state of the art.
Pages 27-29 of the instant specification, lists example disorders applicant intends to prevent.
There are no working examples of such preventive procedure in a man or animal in the specification
The claims rejected are drawn to the medical prevention and are therefore physiological in nature.
The state of the art is that no general procedure is art-recognized for determining which patients generally will become afflicted with a disorder before the fact.
The artisan using Applicant’s invention would be a board certified physician who specializes in treating diseases.
Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of such a broad scope of disorders generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of the practitioners in that art, Genetech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to use an agent to be able to prevent such a broad scope of diseases. That is, the skill is so low that no compound effective generally against such disorders has ever been found let alone one that can prevent such conditions.
It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved”, and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 214 (CCPA 1970).
The claims broadly read on all patients, not just those undergoing therapy for the claimed disorders and on the multitude of compounds embraced by formula (I).
[2] “Treating” disorders:
The nature of the invention / The breadth of the claims:
The nature of the invention is the method of treating a disorder that is “associated with” the physiological condition of ferroptosis. Ferroptosis is a condition of nonapoptotic cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids and which is present in many diverse medical conditions. See the recent review article “Zhou” for a more thorough discussion of the inter-dependent and inter-connected cell death processes involved in ferroptosis and various pathological disorders and potential pharmacological interventions.
The disorders “associated with ferroptosis” that are within scope of the claimed treatment include not only those particular disorders highlighted for example in the Zhou review together with those listed in the specification and in dependent claims 27-29, but also any disorder that also occurs in a patient as a result of having at least one of those particular disorders. For example, pain, depression, bacterial infection, etc. may be “associated with” a ferroptosis condition.
The claims are drawn to the treatment of the disorders with the compounds of formula (I) of claim 1 which are described as modulators of the lipid repair enzyme GPX4 which is involved in the physiological signaling processes that occur in ferroptosis. See Zhou, section 2.1.3 which describes the complex processes and where this particular enzyme fits into the compromised antioxidant systems which antagonize ferroptosis. The broad scope of compounds used in the method includes a very large number of molecules across a diverse range of size, shape, polarity, lipophilicity, hydrogen bonding properties, etc. Notably, even the core structure of the claimed compounds is not consistent, since Z, X and Y can ultimately result in the formation of various different heterocyclic cores which would not be expected to have similar activity.
The state of the prior art: The state of the prior art is that it involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific disease). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face. Further, the prior art is aware of many different and varied protein kinases which may act on many different and varied diseases.
The prior art broadly suggests that compounds which modulated GPX4 might have utility as therapeutic agents in numerous disease states (Zhou). Zhou discusses the treatment of conditions such as cancer, neurodegenerative diseases, organ injury, infectious diseases, autoimmune diseases, metabolic disease and skin diseases (See Section 4). However, “the role of ferroptosis in disease pathogenesis, both through its activation and inhibition, highlights lipid metabolism, iron homeostasis, and redox systems as key pathways for therapeutic intervention” (Section 5, p. 17). The reference goes on to state “Although overwhelming lipid oxidation and subsequent plasma membrane rupture are recognized as central events in ferroptosis, the intricate cellular biology underlying this process, including intracellular lipid transport between organelles, the propagation of lipid peroxidation reactions within cells, the degradation of specific lipid species during peroxidation, and the role of fragmented oxidative products in membrane rupture—remains to be fully elucidated” (Zhou, p. 23). “Additionally, much of the current understanding of ferroptosis stems from studies in cultured cancer cells. More research is needed to explore ferroptosis in cell lines from other diseases and normal tissues, as these may involve distinct mechanisms” (Zhou, p. 23). Importantly, there is no established nexus between the treatment of the entirety of the claimed diseases and the physiological process of ferroptosis. Zhou concludes “further research is required to identify and quantify endogenous triggers and inhibitors of ferroptosis across various pathophysiological states” (p. 23).
The state of the art does not appear to provide any evidence as to a successful treatment of a broad scope of conditions as recited in the instant claims.
The predictability in the art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instantly claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to the therapeutic effects of all disorders “associated with ferroptosis”, whether or not the modulation of a particular protein kinase receptor would make a difference in the disease. Hence, in the absence of a showing of a nexus between any and all known disorders “associated with ferroptosis” and the mechanism of action of the instantly claimed compounds, one of ordinary skill in the art is unable to fully predict possible results from the administration of the compound of Formula (I) due to the unpredictability of the role of modulation of protein kinase receptors.
The presence or absence of working examples / The amount of direction or guidance present: The instantly claimed compounds have been tested for neurotoxicity and excitotoxicity in the presence of ferroptosis inducers in HT22 cells (Example II.1). An in vivo assay of 24 compounds tested shows a cytoprotective effect against cisplatin-induced cell death. Such an examples do not provide sufficient guidance to use all of the compounds within scope of the claims in all disorders “associated with ferroptosis” in patients. This example shows at best that the compound represents a lead compound requiring further study and optimization in order to provide for any effective therapeutic treatment.
The quantity of experimentation needed:
The amount of experimentation would be undue because it would require determining which of the disorders in the scope of the instant claims would be reasonably treated with the compounds of the claims. Since, as discussed above, it is not routine to determine how a chemical will act on the processes of nonapoptotic cell death to treat different disorders, knowing only that the compound of the instant claims inhibit a particular enzyme would mean that significant experimentation would be required to determine which disorders the compound could treat. This is because one cannot extrapolate between the activity of the compound as an enzyme inhibitor and the treatment of all the disorders claimed and since there is little guidance (in both the prior art and the specification) with respect to the use of such compounds for the disorders claimed.
The level of the skill in the art: The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
An ordinary artisan in the area of drug development would have experience in screening chemical compounds for particular activities. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems such as programmed cell-death.
Thus, the specification fails to provide sufficient support of the broad use of the compounds of Formula (I) for the treatment or prevention of any disorder “associated with ferroptosis”. As a result necessitating one of ordinary skill to perform an exhaustive search for which diseases can be treated by which compound of Formula (I) in order to practice the claimed invention.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, one of ordinary skill in the art would have to engage in undue experimentation to test which diseases can be treated by the compounds of the instant claims, with no assurance of success.
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.
Claim(s) 17-25, 27-30 and 33-36 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Le Cann et al.
The prior art teaches the instantly elected species sibriline (Sib) as an inhibitor of necroptosis, which inhibits necroptotic cell death in human or mouse cells while not protecting from caspase-dependent apoptosis (see Abstract). The reference goes on to teach that Sib is a RIPK1 inhibitor and was administered to mice and found to have a therapeutic effect against concanavalin A-induced hepatitis. With respect to instant claim 30, the prior art teaches an in vitro method involving the addition of Sib to FADD-deficient Jurkat cells, which reads on the claimed biological material (p. 3052), where the addition is taught to decrease cell death.
Notably, any effect of the claimed administration (e.g. inhibiting ferroptosis or treating/preventing a disease associated therewith) would necessarily occur upon administration of an anticipatory compound to an anticipatory patient population. Finally, since the prior art teaches the administration of sibriline to mice, the anticipatory compound necessarily has the claimed effect recited in the instant claims, including for the treatment of hepatitis. Further, since the instant claims recite prevention of diseases, it is noted that the patient to which the compound is administered need not actually have the disease recited in the claims in order for the administration to be anticipatory. Accordingly, since the art teaches each required limitation of the instant claims, the claims are anticipated.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699