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 .
Please note that the Examiner for this application has CHANGED.
The Applicants’ Amendment to the Claims filed on February 10, 2026 is entered.
This is the First Office Action on the Merits of US18/050,423 filed on 10/27/2022 which claims US priority benefit of US Provisional 63/272,570 filed on 10/27/2021. The Filing Receipt filed on 08/23/2023 is controlling.
Claims 1-209 are canceled. Claim 245 is new.
Claims 210-245 are pending.
Claims 232-244 are withdrawn to non-elected invention Group.
Claims 228-229 are withdrawn to non-elected Species claims.
Claims 210-227, 230-231 and 245 are under examination.
Election/Restrictions
Applicant’s election without traverse of Group I (e.g., claims 210-231 and 245) in the reply filed on February 10, 2026 is acknowledged.
Claims 232-244 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 10, 2026.
Applicant’s election without traverse of species claim 29:
c) structure (1) or an ionized form thereof (claim 230)
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as the one type of Species of Synthetic compound from among those recited in claims 228-230: a.) Formula (I) (claim 228); b) Formula (1-k) (claim 229); and c) structure (1) or an ionized form thereof (claim 230), in the reply filed on February 10, 2026 is acknowledged.
Claims 228 and 229 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Species claims, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 10, 2026.
Drawings
The drawings are objected to because some of the text in Figures 1, 2 and 8 is illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application US Provisional 63/272,570 filed on 10/27/2021, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The ‘570 Provisional does not support the presently claimed composition comprising a complex suspended in a solid medium, the solid medium comprising vitreous ice, wherein the complex comprises a protein and a generic synthetic compound, wherein the protein is a ryanodine receptor 1 protein (RyRI) or mutant thereof. Specifically, the ‘570 Provisional recites in para 0012
a co-crystal comprising a ryanodine receptor type 1 or a fragment thereof, and a Rycal compound of formula (1). Using cryogenic electron microscopy, the structure of RyR1 at 2.45 Å was resolved, revealing a binding site in the cytosolic shell. This site is formed by a cleft in the RY1&2 domain that binds Compound 1 and ATP. In some embodiments, a co-crystal comprises a Rycal compound, such as Compound 1, bound to the RY1&2 domain of RyR1 cooperatively with ATP.
Thus, it is considered that the ‘570 Provisional supports dependent claim 230 which recites the synthetic compound being the Rycal compound structure of formula (1) but does not support the claimed complex comprising an RyR1 and a generic synthetic compound.
Present claim 230 receives an effective filing date of 10/27/2021.
However, present claims 210-227, and 245, which are generic to the type of synthetic compound, receive priority to 10/27/2022.
Also, regarding claim 231, the ‘570 Provisional does not disclose the limitation of present claim 231 regarding 3-D structures of TABLE 3 of the instant ‘423 application.
Thus, present claims 210-227, 231,and 245, receive an effective filing date to instant application US18/050,423 filed on 10/27/2022.
Information Disclosure Statement
The six IDS statements filed on 12/01/2025 have been considered by the examiner.
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.
Claims 216, 218, 219-220, 222, 225, 231, and 245 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.
Claims 216, 219, and 231 are indefinite because they reference Tables found in the Specification. 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. Incorporation by reference is a necessity doctrine, not for applicant's convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP 2173.05(s). The claims 216, 219, and 231 cannot reference material in the Specification. The claims must be complete in themselves. See additional reasons why claims 216, 219, and 231 are indefinite just below.
Regarding claim 216 the phrase “wherein the RY1&2 domain has a three-dimensional structure according to TABLE 2” renders the claim indefinite. A review of TABLE 2 in the specification finds that TABLE 2 is not complete to meet the limitation of clearly limiting the three-dimensional conformation of the RY1&2 domain. For example, note that legends to the Table are not actually part of the Table and thus the meanings within the Table are unclear.
Regarding claim 218, the term “W996 of the protein” renders the claim indefinite because there is no prior reference in the claim to a SEQ ID NO corresponding to the “W996” of a protein.
Also, claims 219-220 are indefinite for the same reasoning as claim 218 because they depend from claim 218 and are not remedial.
Also, regarding claim 219, the phrase “wherein the ATP molecule has a three-dimensional conformation according to TABLE 4 renders the claim indefinite. A review of TABLE 4 in the specification finds that TABLE 4 is not complete to meet the limitation of clearly limiting the three-dimensional conformation of the ATP molecule. For example, note that legends to the Table are not actually part of the Table and thus the meanings within the Table are unclear.
Regarding claim 222, the claim lacks sufficient antecedent basis for the term “a second ATP molecule” in line 3. Claim 22 depends from claim 213 which does not require an ATP molecule. Claim 22 recites the phrase: “the complex further comprises a second nucleoside-containing molecule bound to a C-terminal domain of the RyR1 protein, wherein the second nucleoside-containing molecule is a second ATP molecule”. As presently written it is unclear whether the claim intends to required two ATP molecules.
Regarding claim 225, the terms “W882 of the protein” and “H879 of the protein” render the claim indefinite because there is no prior reference in the claim to a SEQ ID NO corresponding to the W882 or H879 of a protein.
Regarding claim 231, the phrase “wherein the synthetic compound has a 3-D conformation according to TABLE 3” renders the claim indefinite. A review of TABLE 3 in the specification finds that TABLE 3 is not complete to meet the limitation of clearly limiting the three-dimensional conformation of the synthetic compound. For example, note that legends to the Table are not actually part of the Table and thus the meanings within the Table are unclear.
Regarding claim 245, the terms “W882A” and “C906A” render the claim indefinite because there is no prior reference in the claim to a SEQ ID NO corresponding to the “W882A” or the “C906A.
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.
Claims 210-227, 230-231 and 245 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.
Claims are drawn to a composition comprising a complex suspended in a solid medium, the solid medium comprising vitreous ice, wherein the complex comprises a ryanodine receptor 1 protein (or mutant thereof) and a generic synthetic compound. Dependent claims require specific binding and conformational properties for the RyR1 mutant protein and for the synthetic compound within the claimed complex. Thus, the claims require the critically essential element of a complex comprising a combination an RyR1 mutant (variant structure) and a generic synthetic compound but without sufficient structure correlated to such RyR1 variants or generic synthetic compound to show possession of the such genus of critically essential elements.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include:
(1) Actual reduction to practice,
(2) Disclosure of drawings or structural chemical formulas,
(3) Sufficient relevant identifying characteristics such as:
i. Complete structure,
ii. Partial structure,
iii. Physical and/or chemical properties,
iv. Functional characteristics when coupled with a known or disclosed structure, and correlation between function and structure,
(4) Method of making the claimed invention,
(5) Level of skill and knowledge in the art, and
(6) Predictability in the art.
Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
The level of skill in the art of forming complexes comprising a RyR1 protein and a Rycal compound of formula (1) was high before the effective filing date of the presently claimed invention. See Yan et al (US 2013/0281512, published 10/24/2013) and Mark et al (WO-2015014666-A1, published 02/05/2015). For example, Marks et al teaches the Rycal synthetic compound of the elected species. Further Marks et al state that “typically, the agents of the invention are named Rycals which are well known in the art. However, Marks et al does not show a genus of synthetic compounds other than Rycal compounds. Further, Marks et al does not disclose mutant RyR1 proteins that bind the Rycals. Marks et al teach such compound as a stabilizer of RyR1 and calstabin. Yan et al teach the synthetic compound of the elected species, as a compound for use in treat disorders and diseases associated with ryanodine receptors RyR1 and RyR2 (aka RyRs) that regulate calcium channel functioning in cells. Yan et al disclose that Rycal compounds that bind RyRs may be very unstable and thus individual compounds must be tested for binding to RyR1 for therapeutic used. Yan et al also teaches the addition of ATP in an example studying the binding of calstabin 1 to RyR1, (Example 2; para 0141-0172; 0184). However, neither Marks et al or Yan et al provide a representative set of such RyR1 variants that may bind with a representative set of generic synthetic compounds so that one of ordinary skill in the art would be able to envision whether a give RyR1 protein would possess the required functional properties of binding a given generic synthetic compound without performing trial and error screening methods.
For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. The MPEP states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not a sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP § 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as be structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXlS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these.
The specification describes examples of RyR1 protein complexed with a synthetic compound of Formula I, however the specification does not convey to the skilled artisan that Applicants were in possession of the claimed genus of RyR1 variants complexed with a genus of synthetic compounds as encompassed by the claims.
The specification teaches some examples of RyR1 mutants/variants complexed with a specific Rycal compound structure of formula (1). However, the claims do not describe the above genus with any structure or structure/function correlation for the vast number of potential species of mutant RyR1 proteins and generic synthetic compounds that can be used to predict the structure of other species within the claimed genus.
The listed species in the instant specification and found in the state of the prior art do not adequately support the claimed genus because the specification or state of the art does not provide common identifying characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these for the RyR1 mutants/variants coupled to a generic synthetic compound.
Although the claims may recite some functional characteristics, the claims lack written description because there is no disclosure of a correlation between function and structure of the compounds beyond those compounds specifically disclosed in the examples in the specification. Moreover, the specification lack sufficient variety of species to reflect this variance in the genus. While having written description of complexes comprising the RyR1 protein and specific mutants described in the specification complexed with the specific rycal ligand compounds shown in the specification to bind such RyR1 proteins identified in the specification tables and/or examples, the specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims. Given this lack of description of representative species encompassed by the genus of the claim, the specification does not sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the entire scope of the claimed 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 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 210-213, 217, 223, 227, and 230 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al (US 2013/0281512, published 10/24/2013), in view of Mark et al (WO-2015014666-A1, published 02/05/2015), in view of Liu et al (J Biol Chem., published September 11, 2005; Vol 280, No. 45: pages 37941-37947).
Regarding base claim 210, Yan et al teach the synthetic compound of the elected species, as a compound for treating disorders and diseases associated with ryanodine receptors (RyRs) that regulate calcium channel functioning in cells.
Regarding base claim 210, Marks et al teach a complex comprising RyR1 and the synthetic compound of the elected species. Marks et al teach the synthetic compound as a stabilizer of RyR1 and calstabin.
Regarding claims 210, 227, and 230, each of Yan et al and Marks et al disclose the synthetic compound is (1) just below.
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Regarding claim 227, Yan et al and Marks et al disclose that the synthetic compound comprises a benzothiazepine moiety. For example, the structure just below is a benzothiazepine compound which is part of the elected species compound shown below.
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Regarding claims 213 and 217, Yan et al also teaches the addition of ATP in an example studying the binding of calstabin 1 to RyR1, (Example 2; para 0141-0172; 0184).
Regarding claim 223, Marks et al discloses that the complex further comprises one or more of calmodulin, calstabin, caffeine, or a Ca2+ ion. Marks et al teach a complex comprising RyR1 and the synthetic compound of the elected species. Marks et al teach the synthetic compound as a stabilizer of RyR1 and calstabin.
However, both Yan et al and Marks et al differ from the instant claims because they do not disclose the complex in a solution suspended in vitreous ice.
Liu et al teach RyR2 functions as a calcium release channel in the heart (Introduction, para. 2). Liu also teaches an example of RyR2 proteins in vitreous ice applied to a cryoelectron micrograph grid (Figure 3). Liu teaches the RyR2 protein in the presence of buffer (Experimental procedures, Cryo-EM para.) and Ca²⁺ ions in order to study its binding activity (Fig 2a, and Results para. 3). Regarding claim 210-212, and 223, Liu et al discloses that the composition is prepared by a process comprising vitrifying an aqueous solution applied to an electron microscopy grid, wherein the aqueous solution comprises the protein and the synthetic compound. Liu et al discloses that the aqueous solution includes one or more of caffeine, a Ca2+ion, sodium adenosine triphosphate (NaATP), or calmodulin. (Experimental procedures, Cryo-EM para; Fig 2a, and Results para. 3 .)
Also, regarding claims 211 and 212, these claims have product by process language and are interpreted in light of MPEP 2113(I). "Even though product-by- process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to apply the methods for cryo EM as taught by Liu et al to the compounds of Yan et al and Marks et al for the rationale to study the interaction and reactions using electron microscopy.
It would then be obvious to suspend the solution, along with Ca²⁺ and a buffering agent as well as any other compounds involved in the biological reaction, in vitreous ice, as taught by Liu, because the cited references are in the same field of studying binding sites and activities of ryanodine receptors (RyRs) that regulate calcium channel functioning in cells.
In view of the high level of skill of one of ordinary skill in the art before the effective filing date of the presently claimed invention it is considered that one of ordinary skill in the art having the cited references would have had a reasonable expectation of success to apply cryo EM methods as disclosed in Liu et alto the compounds of Marks et al to arrive at the presently claimed invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
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