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 in reply to the Applicant’s Arguments/Remarks filed on 04 June 2026 for application 18/335,687. Currently, claims 1-17, 19, 27-29 and 41-66 are pending.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection the previous office action is set out below.
35 U.S.C. 102, 103, and Double Patenting
Applicant’s arguments to claims 1-9 were found persuasive and the rejection has been withdrawn.
Consequently, the rejections of claims 19, 27-28, 59 and 53 are no longer relevant and have been withdrawn.
Additionally, the objections on claims 10-17 are no longer relevant and have been withdrawn.
REJECTIONS – MAINTAINED & NEW
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.
(Maintained) Claims 29, 62, and 66 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A review of the rejected claim language indicates that these claims are drawn toward "a method for treating or preventing a disease from the group consisting" in this case, thrombosis, by species election, "comprising administering a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof to the mammal" in the case of claim 29. Similar language is utilized in claims 62 and 66. A description of the term "a method of treating or preventing a disease or disorder... may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California V. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California V. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states "An adequate written description of a DNA requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention". Hence, an adequate written description of the components requires more than a mere statement that it is part of the invention. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984). In Applicant's originally filed specification, background art, expounds upon thrombus formation including three important factors specified to be changes in blood components, changes in properties of vascular wall, and changes in blood flow. The specification also identifies that arterial blood flow is laminar and therefore platelet aggregation primarily occurs near the vascular wall and one means of triggering this aggregation is arteriosclerotic plaque rupture, which is further compounded by platelet activation signaling, i.e. von Willebrand factor and collagen interaction. The applicant also notes in the instant specification that there are many factors that activate platelets and induce platelet aggregation, but all aggregation is terminally characterized by the cross- linking of platelets. As such, drugs whose mechanism of action interferes with the signaling pathway of platelet activation carry a bleeding risk. The applicant also describes PLD1 and PLD2, enzymes that contribute to various signaling pathways with regulatory and functional properties such as cell proliferation, cell death and inflammation, having phenotypic anti- thrombotic effects in in vitro murine cell knock-out experiments. Additionally, the specification notes that activation of PLD1 and PLD2 are thought to contribute to a number of pathologies with over-expression and increase activities being observed in a number of cancers. However, the applicant only demonstrates applications in two instances: biochemical inhibition of the full-length human PLD1 and PLD2 proteins derived from encoded HEK-293 derived expi293f cells. Applicant does not demonstrate that the product is capable of the claimed method of "treating or preventing the disease of thrombosis" to the breadth and scope of which broadest reasonable interpretation requires. The limited biochemical data leads one to conclude that the applicant was not in possession of a method of treating or preventing thrombosis. Estevez et al. (New concepts and mechanisms of platelet activation signaling, Physiology 2017, 32, 162-177) teaches that thrombosis, and therefore platelet aggregation, is the product of numerous factors, has different etiologies such as injury or trauma, medical conditions, lifestyle influences, and genetic predispositions. These idiopathic factors undermine the concept that biochemical results are prophetic to the final therapeutic application of the invention in a mammal. Whether the specification shows that the inventor was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structures, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. "In contrast, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predicable which are known to one of ordinary skill in the art, more evidence is required to show possession". One of skill in the art would not recognize from the disclosure that the applicant was in possession of "a method of treating or preventing a disease..." as claimed.
Additionally, it is also known that there are significant challenges translating biochemical, in vitro, and in vivo studies to a clinical setting, and that not all biochemical, in vitro and in vivo studies can be directly translated to the clinical setting. Indeed, J. M. McKim (Building a tiered approach to in vitro predictive toxicity screening: a focus on assays with in vivo resistance, Combo. Chem. & High Throughput Scr. 2010, 13, 188-206) emphasizes a truism of the pharmaceutical industry that persists to this day, is the failure of over 90% of promising new drug candidates due to unanticipated adverse effects or a lack of efficacy in humans, contrary to anticipated results based on prior biochemical, cell, or animal models (Introduction). As the specification discloses working examples only performed biochemically, one of skill in the art would not recognize that the Applicant was in possession of "a method of preventing or treating thrombosis" in an in vivo, much less a clinical, setting.
(Maintained) Claims 29, 62, and 66 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 thrombosis by inhibiting purified full-length human PLD1 and PLD2 proteins, does not reasonably provide enablement for treating thrombosis in a mammal, comprised of administering "a compound". 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, 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. See MPEP § 2164.01 (a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art could not practice the invention without being burdened with undue experimentation based on the information provided by the applicant. A discussion of these factors as they relate to the pending claims is as follows:
(A) Breadth of claims & (B) nature of invention –
The applicant's claims are broad. For example, claim 29 is directed to " a method of treating or preventing a disease, selected to be thrombosis..., comprising the step of administering a therapeutically effective amount a compound to a mammal" As the genus of mammal is very broad, including not only animals that are commonly used for laboratory testing such as mice, rats, dogs of various breeds, pot-bellied pigs and monkeys, but can very obviously include humans along with any number of other uncommon possibilities such as bears, whales, elephants, etc. While the Applicant discloses the potential application of the product in the inhibition of purified PLD1 and PL2 enzymes, they are not unto themselves demonstrative single agent means of treating thrombosis. For example, Estevez et al. (New concepts and mechanisms of platelet activation signaling, Physiology 2017, 32, 162-177) teaches that platelet activation requires intracellular signal transduction initiated by platelet receptors for adhesion proteins and soluble agonists that, at the time of publication, was described as an increasingly complex and sophisticated picture of platelet signaling and amplification network. Estevez divides platelet activation signaling into four phases including 1) divergent early receptor signaling induced by not only classic soluble platelet agonists but also adhesion receptor ligands and inflammatory stimuli, 2) convergence of early signaling pathways on common intermediates and signal amplification networks, 3) inside-out signaling leading to activation of the main platelet adhesion receptor, the integrin α₁₁bβ₃, which mediates stable platelet adhesion and aggregation, and 4) integrin outside-in signaling, which greatly amplifies platelet activation and thrombus size. (pg. 1). Indeed, the Applicant themselves note that thrombosis is influenced by several factors including physiological and signaling factors. As the specification discloses working examples only performed in biochemical assays, one of ordinary skill in the art would not recognize that the evidence provided by the Applicant in the instant specification is "a method of preventing or treating thrombosis" and can be used to prevent and treat the possible breadth of what is a diverse disease that appears to arise from multiple factors and pathways.
(C) The state of the prior art –
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05(a). As taught by Estevez, thrombosis and therefore platelet aggregation is the product of numerous factors, has different etiologies such as injury or trauma, medical conditions, lifestyle influences, and genetic predispositions. Therefore, it is reasonable to conclude that the current state of the art is highly unpredictable, indicating that more details, working examples, and guidance would be required to practice the invention as disclosed for treating and/or preventing thrombosis as claimed.
(D) The level of one of ordinary skill in the art –
MPEP 2141.03 states (in part), "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. V. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. At 1396, 82 USPQ2d at 1396. The "hypothetical person having ordinary skill in the art' to which the claimed subject matter pertains would, of necessity, have the capability of understanding the scientific and engineering principles applicable to the pertinent art." Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) disagreeing with the examiner's definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering).
These hurdles render application of "a method for preventing or treating thrombosis comprising the step of administering a therapeutically effective amount of a compound" to a very high level of unpredictability. The lack of significant guidance from the present specification makes practicing the claimed invention unpredictable. Where the predictability in the art is low, the Applicant is required to provide greater disclosure and guidance to comply with the enablement requirement. MPEP § 2164.03.
(E) Existence of working examples & (F) amount of direction or guidance by the inventor –
As previously established by Estevez, thrombosis and therefore platelet aggregation is a complex and sophisticated process. Conversely, the specification does not demonstrate, also as previously established, a means to prevent or treat thrombosis generally in possible etiologies in all mammals, instead only providing results of biochemical inhibition of PLD1 and
PLD2 enzymes. Therefore, the applicant has not provided sufficient guidance to enable one
of skill in the art to make and use the claimed invention in a manner reasonably correlated
with the scope of the claims.
(G) Quantity of experimentation needed to make or use the invention –
Taken together, the prior art demonstrates that the disease of thrombosis, arises from multiple factors and etiologies. This covers a breadth and scope of material that is far from adequately addressed in the instant specification. While the specification demonstrates inhibition on the specific enzymes, it does not demonstrate how "a compound" would be able to matriculate into a preclinical candidate, much less a new investigational drug with a reasonable chance of success to reach the status as a demonstrative drug containing therapeutically efficacious properties. Even if the compound was not being considered from human treatment, there are, as established by McKim, numerous hurdles that must be overcome for use in the broad category of mammals including the most basic of demonstrating efficacy in vitro and in vivo, which is not a guaranteed, linear progression. This constitutes undue experimentation. Therefore, the lack of working examples commensurate in scope to the claimed invention and the unpredictability in successful application as described by claims 29, 62 and 66, and as described in the specification, as filed, does not provide enablement for the claimed method of use.
In conclusion, the claimed invention does not provide enablement for the application in the method of use in preventing or treating thrombosis. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation is undue, due to the broad scope of the claim, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of ordinary skill in the art would be forced into undue experimentation to practice the claimed invention.
Allowable Subject Matter
Claims 1-17, 19, 27-28, and 41-61 and 63-65 are allowed.
Reasons For Allowable Subject Matter
The following is an examiner's statement of reasons for allowance: the following is a statement of reason for the indication of allowable subject matter: structure as defined by compound 57 and other analogous structures in claims 41-49 were not taught in the prior art in a 100% embodiment. The closest match are disparate structures as disclosed by Rosenblum et al. (Synthesis of dihydrooxadiazinones and study of geometrical isomerism in α-ketol carbethoxyhydrazones, JACS Legacy, 1963, 85, 3874-3878), Ellermann et al. (Dihydrooxadiazinones for the treatment of hyperproliferative diseases, WO 2020/157188 A1, 2020), and Metrick et al. (Human PLD structures enable drug design and characterization of isoenzyme selectivity, Nat. Chem. Biol. 2020, 16, 391-399, entered in IDS on 10 October 2023) without encompassing all aspects. No examples of connected structures were found in the prior art search.
As the claimed compounds are, as described by the instant specification, as enabled in inhibiting PLD1 and PLD2, claims 60-61, dependent on claims 41-49, are allowed. Claims 50-58 are substantially similar structures to those in claims 40-49, but further limit the claims through claiming the free base. Claims 64-65, similarly to claims 60-61 enabled in inhibiting
PLD1 and PLD2, dependent on claims 50-58, are allowed.
Applicant’s arguments toward the 35 U.S.C. 103 rejections of claims 1-9 were found persuasive. Therefore, the independent base claim is allowable.
Therefore, the prior art neither anticipates nor reasonably makes obvious the claimed invention and therefore, the claimed invention is deemed novel and unobvious over the prior art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled "Comments on Statement of Reasons for Allowance."
Response to Arguments
The office kindly thanks the Applicant for their consideration and arguments to the previous office action. Responses are detailed below.
Applicant's arguments filed 04 June 2026 have been fully considered but they are not persuasive.
Firstly, the Examiner thanks the Applicant for their understanding cited in the instant specification.
On pg. 3 – Claim Rejections – 35 U.S.C. § 112(a) – Written Description, filed 04 June 2026, the Applicant argues:
… the compounds of the present application demonstrate biochemical inhibition of full-length human PLD1 and PLD2 proteins derived from encoded HEK-293 derived expi293f cells… reasonably conclude that the claimed compounds are capable of the claimed methods of treating or preventing the disease of thrombosis…Estevez does not disclose or discuss such factors other than injury and provides no teaching of unpredictability…. Estevez supports, rather than undermines, the proposition that targeting specific signaling pathways is a viable approach for addressing thrombosis… written description requirement is satisfied when the specification reasonably conveys to those skilled in the relevant art that the inventor had possession at the time of filing…
Applicant’s suggestion that at least in vivo data is not necessary to show possession is unconvincing on the face. The Examiner agrees that single biological target therapy is a reasonable choice for those undertaking the development of a pharmaceutical therapy. However, the numerous hurdles in vitro efficacy, in vivo efficacy in any number of animal models, pharmacokinetics, metabolism, drug solubility, permeability, any number of pharmacodynamic models that must be developed and proven to work, toxicology in animals, hERG and CYP tolerance, etc, amongst many others, renders it unconvincing that the Applicant’s claimed compounds, not the biological target, are capable of being utilized to the extent that broadest reasonable interpretation requires. As the subject to be treated or prevented are mammals, humans are necessarily a requirement within the bounds of that limitation, with the greatest number of challenges and hurdles. This is only in the myopic view of thrombosis, without considering the other limitation of cancer, which is a very broad genus that currently has no known means of being prevented, only treated.
On pg. 4 - Claim Rejections – 35 U.S.C. § 112(a) – Enablement, filed 04 June 2026, the Applicant argues:
… office improperly applies the enablement requirement by seemingly requiring proof that a claimed compound can progress into a preclinical or investigational drug with a reasonable chance of success… non-patent documents 7 and 8 provide in vivo phenotypic analyses … correlate with the claimed methods of treating or preventing thrombosis in that they establish the role of PLD1 and PLD2 in the therapeutic context…
The Examiner’s response is the same as above: while the examiner agrees that NPL establishes PLD1 and PLD2 as worthwhile targets of therapy, it is application of the claimed compounds, specifically in the treatment of thrombosis, never mind the extremely broad genus of cancer, that has not been enabled in all mammals including humans.
Applicant’s arguments, see pgs. 6-8 Claim Rejections – 35 U.S.C. § 103, claims 1-9, filed 04 June 2026, with respect to claims 1-9 have been fully considered and are persuasive. The rejection of claims 1-9 has been withdrawn.
Applicant’s arguments, see pgs. 8-9, Claim Rejections – 35 U.S.C. § 103, claims 19, 59 and 63, filed 04 June 2026, with respect to claims 19, 59, 63 have been fully considered and are persuasive. The rejection of claims 19, 59, 63 has been withdrawn.
Applicant’s arguments, see pg. 9, Claim Rejections – 35 U.S.C. § 103, claims 27-28, filed 04 June 2026, with respect to claims 27-28 have been fully considered and are persuasive. The rejection of claims 27-28 has been withdrawn.
Applicant’s arguments, see pg. 9, Allowable Subject Matter, filed 04 June 2026, with respect to claims 10-17 have been fully considered and are persuasive. The objection of claims 10-17 has been withdrawn.
Examiner acknowledges filing of the certified English translation of Japanese Patent Application No. 2022-097544.
Examiner acknowledges filing of the English language copy of the Japanese Patent Office International Search Report (ISR) in International Patent Application No. PCT/JP2023/022253.
Conclusion
Claims 1-17, 19, 27-28 and 41-61 and 63-65 are allowed. Claims 29, 62 and 66 are rejected under 35 U.S.C. 112(a).
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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