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 .
Claims 10-11 and 13 are cancelled.
Claims 1, 4, 6, 12, 14, 17, and 22 are amended.
Claims 1-9, 12, and 14-27 are pending and under examination on the merits.
Priority
Applicant’s claim of priority to International Patent Application PCT/EP2020/061803, filed April 28, 2020, designating the United States of America and published in English as International Patent Publication WO 2020/221768 on November 5, 2020, which claims the benefit under Article 8 of the Patent Cooperation Treaty to U.S. Provisional Patent Application Serial No. 62/840,091, filed April 29, 2019, U.S. Provisional Patent Application Serial No. 62/840,092, filed April 29, 2019, U.S. Provisional Patent Application Serial No. 62/840,094, filed April 29, 2019, U.S. Provisional Patent Application Serial No. 62/863,544, filed June 19, 2019, U.S. Provisional Patent Application Serial No. 62/934,136, filed November 12, 2019, U.S. Provisional Patent Application Serial No. 62/934,181, filed November 12, 2019, and U.S. Provisional Patent Application Serial No. 62/934,133, filed November 12, 2019,
is noted.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/24/2025 has been considered by the examiner.
Withdrawn Objections and Rejections
The objection to the specification is withdrawn in light of the corrective amendments dated 09/04/2025. The objections to claims 10-11 and 17 are withdrawn in light of the corrective amendments dated 09/04/2025. in light of the corrective amendments dated 09/04/2025. The rejection of claim 6 under 35 USC §112(b) is withdrawn in light of the corrective amendments dated 09/04/2025. in light of the corrective amendments dated 09/04/2025. The rejections of the claims under 35 §102 and §103 are withdrawn in light of the new limitations added by the claim amendments dated 09/04/2025.
New-Claim Interpretation
The claimed arrangements are being interpreted to conform to one of the arrangements depicted in schematic figures 1-3 so as to find support in the disclosure as filed.
New-Claim Objections
Claim 4 is objected to because of the following informalities: “…in which binding domain…” as recited in line 1 should instead read “…in which the binding domains…”. Appropriate correction is required.
New-Claim Rejections - 35 USC § 112
35 USC § 112(a)
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 1-9, 12, and 14-27 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims broad genera of binding domains (also at times called binding units, noting that there is no distinction drawn between the two seemingly interchangeable terms throughout the specification) and second ligands. The specification provides that “…[s]uch binding domains vary in length from between about 25 amino acids up to 500 amino acids and more. Many binding domains can be classified into folds and are recognizable, identifiable, 3-D structures…[a] binding domain can thus be derived from a naturally occurring molecule, e.g. from components of the innate or adaptive immune system, or it can be entirely artificially designed…,” (see for example, page 19 of the specification at lines 15-30). There is no closed definition provided. The specification further provides that “a second ligand for the translayer protein may optionally be part of a protein complex….the second ligand can be any suitable ligand…,” (see for example, page 36 of the specification). The breadth of what is encompassed by these terms is clearly expansive.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only disclosed the binding domains/binding units/second ligands shown in Table 1 and further explained in the examples (note that the binding domains must function in the claimed GPCR arrangement(s) and further necessitate description of a second ligand capable of interacting with both the translayer protein and the binding domain/binding unit. Thus, given the substantial structure variation within the genera of the claimed binding domain/binding unit and second ligand and the high level of unpredictability in the art, the disclosure of only the limited combinations of binding domain/unit and second ligand of Table 1 (additionally discussed in examples 1-21) (see for example, pages 116-141 of the instant specification) is not deemed to convey adequate written description through demonstration of a structure-function correlation or by provision of a representative number of species.
The state of the art requires a high degree of skill and is unpredictable.
For example, antibodies and fragments thereof are clearly encompassed within the recitation of a binding domain/binding unit. Antibodies are part of a highly skilled and unpredictable art where even a single mutation in the CDRs may alter or abrogate binding (see for example Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969; Rabia, et al (2018, Biochemical Engineering Journal 137:365-374); Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652); and Tsuji et al (2022, J Virol 96:e00071-22)).
The recitation of binding domains/units and of a second ligand further clearly encompasses proteins, which are part of a high skilled and unpredictable art. Listov et al (Opportunities and challenges in design and optimization of protein function. Nat Rev Mol Cell Biol 25, 639–653 (2024)) teach that the primary amino acid sequence determines downstream structure (protein folding), which then determines function (presenting both the inverse folding problem and the inverse function problem (see for example, Figure 1 and its caption; see also Mishra et al (Inaccurate secondary structure predictions often indicate protein fold switching. Protein Sci. 2019 Aug;28(8):1487-1493. doi: 10.1002/pro.3664. Epub 2019 Jun 17)). Expanding on these problems in proteomics, Reardon (Nature 635, 246-248 (2024)) explains that the goal of designing a protein with known and predictable function, binding partners, size, location, and other traits is, for the moment, a dream. Reardon teaches that further challenges in protein design include predicting how a protein, even if it binds to target, will function upon said binding. Reardon teaches that the primary structure (amino acid sequence) of a protein is critical to function, noting that even proteins of similar shape do not execute the same functions, while those with different shapes may carry out the same tasks. Reardon goes on to teach that it is not always apparent which parts of the primary sequence are important; a seemingly useless amino-acid chain on the side of an enzyme, for instance, might affect how tightly a protein can bind to other molecules or its ability to flip between conformational states. Moreover, Reardon explains that when researchers attempt to solve the structure of a protein experimentally, they often end up seeing only the most stable conformation, which is not necessarily the form the protein takes when it is active (see for example, pages 246-247 of Reardon).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody the ability to function as claimed because the instant specification does not provide structural antibody features that correlate with an ability to function in the arrangement as claimed. Likewise, Applicant has not disclosed relevant, identifying characteristics of amino acid sequences/structure that confer upon a protein the ability to function as claimed because the instant specification does not provide structural protein features that correlate with an ability to function in the arrangement as claimed.
Absent a clear description of the at least minimal structural features correlating with an ability to function in the arrangement(s) as claimed which are shared by members of the genera commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied/interchanged such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed. Likewise, the skilled artisan could not immediately envision, recognize, or distinguish which amino acid sequences of proteins may be used or varied to result in a binding domain/unit or second ligand in the claimed arrangement.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences or protein amino acid sequences comprised within the genera of binding domains/units and/or second ligands may be combined/mutated such that the resultant antibody or protein possesses the structural traits capable of functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations or fixed non-antibody protein amino acid sequences, that correlate with the ability to function in the arrangement as claimed, and because the disclosed species of Table 1 (at pages 116-121 of the instant specification) detailed above are not sufficient to describe the claimed genera, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some antibodies/binding domains/peptides that fall within the scope of the claims. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Applicant is further directed to In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention. Therefore, products used in methods are rightfully subject to the written description requirement.
Therefore, the binding domains/binding units and second ligand, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, claims 1-9, 12, and 14-27 are deemed to fail to meet the written description requirement, as presently drafted.
Claims 1-9, 12, and 14-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while providing enabling disclosure of the second ligand/biding domain pairs for indirect binding between the binding domain and the translayer protein using the structure/sequence pairs reflected in Table 1 and examples 1-21 (see for example, pages 116-141 of the instant specification), does not reasonably provide enablement for the broad genera of combinations of encompassed second ligands and binding domains (including ligands and fusions which have yet to be discovered or invented) which facilitate indirect binding of the binding domain and GPCR as claimed (see further, figures 2-3 and their descriptions as disclosed in the instant specification). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or the invention commensurate in scope with these claims.
The specification does not provide any evidence that the claimed arrangement would function with any other protein as the binding domain, any other protein as the second ligand, or any arbitrary combination of binding domain and second ligand. Therefore, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied.
In re Wands, 858F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation.
In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
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.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The claims are drawn to an arrangement comprising a translayer protein which binds indirectly to a binding domain. Note that the genera of second ligand, binding domain/binding unit, and combinations thereof are very broad (as discussed above).
The nature of the invention is a biological/chemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the intended use of the claimed product, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one particular species which other species encompassed by the genus may or may not work; see MPEP § 2164.03.
In regard to Wands factors (C), (D) and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a). Waltenspühl et al (Molecules 2021, 26, 1465. https://doi.org/ 10.3390/molecules26051465) teach that a great number of GPCRs has not yet yielded detailed mechanistic and structural studies, and some physiologically very important receptors are characterized by particularly poor expression and stability properties, making such efforts extremely challenging, if not impossible (see for example, page 1). Further underscoring the unpredictability of the state of the art, Wu et al (Int J Mol Sci. 2024 May 17;25(10):5474. doi: 10.3390/ijms25105474) teach that ligands can have biasing effects involving downstream signals and retainment properties which are important to consider with respect to potential complications arising from different binding and signaling under potentially non-equilibrium assay conditions (see for example, section 3 at pages 3-4). Zimmermann et al (Synthetic single domain antibodies for the conformational trapping of membrane proteins, eLife 7:e34317, obtained from: https://doi.org/10.7554/eLife.34317, available 05/24/2018) teach difficulties associated with predictable generation of conformation-specific binders raised against membrane proteins and propose a system to overcome certain challenges (see for example, the first 3 paragraphs of the Introduction at pages 1-2). However, the difficulties discussed cast doubt on enablement of any generic protein, antibody, or fragment thereof to function, facilitating indirect binding of the translayer protein and binding domain/unit, in the arrangement as instantly claimed.
The teachings of Wu et al and Waltenspühl et al demonstrate that the characterization, and use of/compositions comprising different GPCRs/ligands thereof is unpredictable.
While the level of skill in the art is high, the amount of guidance provided regarding production and functionality of the claimed arrangement(s) is scant. Accordingly, the amount of experimentation required to determine how to make and or use the claimed arrangement(s) is quite extensive.
Due to the large quantity of experimentation necessary to determine how to make and or use the claimed arrangement(s), the lack of direction/guidance presented in the specification regarding the same, the limited number of working examples directed to the same, the complex nature of the invention, the limited state of the prior art, the unpredictability of the effects of complex biological molecules on diseased physiological systems, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention in its full scope, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph. Therefore, only
an arrangement comprising the described combinations of elements set forth in Table 1 and examples 1-21 for use with one another is deemed enabled.
Maintained-Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-9, 12, and 14-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-15 of copending Application No. 17/607,334 in view of PROMEGA (NanoBiT TECHNOLOGY Monitor the Dynamics of Protein: Protein Interactions in Living Cells, 1 January 2016, XP055698299, http://www.eastport.cz/dokumenty/brochure-nonobit-2016-engl_201705241 124428 pdf; as cited in the 10/28/2021 IDS).
This is a provisional nonstatutory double patenting rejection.
As discussed above, Promega teaches an example of the use of NanoBit in living cells measuring real-time ligand-induced ß-arrestin-2 interaction with class A and class B GPCRs. The arrangement comprising a boundary layer (PM) (separating a first and second environment), a translayer protein (GPCR), a first ligand, (agonist), a second ligand (arrestin), and a binding pair (SmBit and LgBit). The binding pair forms a first fusion (GPCR and SmBit) and a second fusion (arrestin and LgBit) (as recited in instant claim 2). Note that the smBit is linked/fused to the translayer protein (GPCR) (forming a first fusion)(see for example, figure 3 and reference generally). Note that the LgBit is linked fused to the ß-2-arrestin (forming a second fusion; note that ß-2-arrestin is naturally occurring) see for example, figure 3 and reference generally). Note that interaction of the SmBit and LgBit generates a functional enzyme with a bright, luminescent (detectable) signal (see for example, figure 1 and the reference generally).
Similarly, co-pending application 17/607,334 claims an arrangement that comprises at least the following elements:- a boundary layer that separates a first environment from a second environment; - a chimeric GPCR according to claim 1; a first ligand for the chimeric GPCR that is present in the first environment; - a second ligand for the chimeric GPCR that is present in the second environment, which second ligand is a binding domain or binding unit that can bind to at least one of the intracellular loops on said chimeric GPCR; and - a binding pair that consists of at least a first binding member and a second binding member, which binding pair is capable of generating a detectable signal, in which the chimeric GPCR is fused or linked, either directly or via a suitable spacer or linker, to the first binding member of said binding pair and in which the second ligand is fused or linked, either directly or via a suitable spacer or linker, to the first binding member of said binding pair, wherein the chimeric GPCR is fused or linked, either directly or via a suitable spacer or linker, to a binding domain or binding unit that can bind to at least one of the intracellular loops of said chimeric GPCR, in which said binding domain or binding unit is ligand is capable of stabilizing and/or inducing a functional and/or active conformational state of the chimeric GPCR upon binding to the chimeric GPCR (see for example, claims 1 and 12-15 of the copending reference application).
The copending reference further claims a fusion protein comprising a binding domain/binding unit that is a ligand capable of stabilizing or inducing a functional/active conformation state of the chimeric GPCR upon binding to said GPCR (see for example, claims 14-15 of the copending reference). The copending reference application does not appear to explicitly provide motivation to use the fusion protein or ligand thereof to facilitate intermediate binding in an arrangement comprising a GPCR, such as the instantly claimed arrangement(s).
However, the specification can be used to determine the utility of a product. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1385 (CAFC 2010) (“Our prior obviousness-type double patenting decisions in Geneva and Pfizer … we found claims of a later patent invalid for obviousness-type double patenting where an earlier patent claimed a compound, disclosing its utility in the specification, and a later patent claimed a method of using the compound for a use described in the specification of the earlier patent”). See also MPEP § 804(II)(B)(2)(a).
The specification of the copending reference application teaches the use of fusion proteins comprising a chimeric GPCR and a binding domain/unit wherein the binding domain/unit is preferably a conformation-inducing binding domain or binding unit, and preferably a conformation-inducing immunoglobulin single variable domain (ISVD) (see for example, pages 1 and 42-43 of the specification of the co-pending reference application). The specification clearly contemplates an arrangement where the claimed arrangement involved indirect binding of the binding domain/unit (or fusion comprising the binding domain/unit) to the GPCR via a second ligand (see for example, figure 3 and pages 87-88) [note that the copending reference teaches the fusions/component combinations enabled in the instant Application; see for example, Table 1 and pages 154-155 of the copending reference noting that copending reference application SEQ ID NO: 7 is identical to instant SEQ ID NO: 15; copending reference application SEQ ID NO: 9 is identical to instant SEQ ID NO: 19; copending reference application SEQ ID NO: 10 is identical to instant SEQ ID NO: 20; copending reference application SEQ ID NO: 8 is identical to instant SEQ ID NO: 16].
Therefore, the artisan would have found it obvious to modify the arrangement of the copending reference application to use a fusion protein for stabilization of the GPCR and would have found it obvious to use one of the disclosed fusions as disclosed, which includes the use where the fusion indirectly binds the translayer protein.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the copending reference application according to Promega. The artisan would have been motivated to make and use the invention as claimed because Promega to take advantage of the functionality taught in Promega and in the entirety of the disclosure of the copending reference application (such as stabilizing and/or inducing a functional/active conformational state of the chimeric translayer protein (GPCR) (see for example, claims 1 and 12-15 of the copending refence application). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses:
Applicant argues that the rejections for double patenting should be withdrawn in light of the new limitations added by the 09/04/2025 claim amendments.
Response: The rejections have been amended to account for the newly added claim limitations. Therefore, the rejections for double patenting as presented in this Office Action are maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Laschet et al (Celine Laschet ET AL: "A dynamic and screening-compatible nanoluciferase-based complementation assay enables profiling of individual GPCR-G protein interactions",
Journal of Biological Chemistry, vol. 294, no. 11, 28 December 2018 (2018-12-28), pages 4079-4090, XP055715055, USISSN: 0021-9258, DOI: 10.1074/jbc.RA118.006231) teach an arrangement comprising a boundary layer (Plasma membrane), a translayer protein (GPCR), a first ligand (yellow ball), a second ligand (a dimer), a binding pair (smBit and lgBit). The binding pair forms a first fusion (GPCR and SmBit) and a second fusion (a dimer and LgBit) (see figure 1) wherein the binding pair (smBit and LgBit are capable of forming a signal as Nanoluc (nano luciferase) which may be used to observe/measure protein-to-protein interactions (see document in its entirety, but for example see page 4 and figure 1).
Gurevich et al (Arrestins: Critical Players in Trafficking of Many GPCRs. Prog Mol Biol Transl Sci. 2015;132:1-14. doi: 10.1016/bs.pmbts.2015.02.010. Epub 2015 Mar 25) teach that arrestin and G-protein compete for overlapping binding sites on the GPCR and otherwise support that arrestin directly binds GPCR (see reference in its entirety).
Chaly et al (The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1. Elife. 2016 Feb 1;5:e12397. doi: 10.7554/eLife.12397) teach that the Melanocortin Receptor Accessory Protein 2 (MRAP2) is an important regulator of energy homeostasis and its loss causes severe obesity in rodents. MRAP2 mediates its action in part through the potentiation of the MC4R, however, it is clear that MRAP2 is expressed in tissues that do not express MC4R, and that the deletion of MRAP2 does not recapitulate the phenotype of Mc4r KO mice. Consequently, they hypothesized that other GPCRs involved in the control of energy homeostasis are likely to be regulated by MRAP2. Chaly et al identified PKR1 as the first non-melanocortin GPCR to be regulated by MRAP2. We show that MRAP2 significantly and specifically inhibits PKR1 signaling. They also demonstrated that PKR1 and MRAP2 co-localize in neurons and that Mrap2 KO mice are hypersensitive to PKR1 stimulation. This study not only identifies new partners of MRAP2 but also a new pathway through which MRAP2 regulates energy homeostasis.
The written opinion of the International Search Authority for application PCT/EP2020/061803 (as cited in the 10/28/2021 IDS) is further deemed to recited pertinent teachings/art regarding the instant claims.
WO2014118297A1 (as cited in the 10/28/2021 IDS) is further deemed to recited pertinent teachings/art regarding the instant claims.
Sachdev et al (Nat Commun 15, 4687 (2024). https://doi.org/10.1038/s41467-024-49068-5) is deemed relevant.
Cheloha et al is deemed relevant (Nat Commun. 2020 Apr 29;11(1):2087. doi: 10.1038/s41467-020-15884-8) is deemed relevant..
Miao et al (Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):3036-3041. doi: 10.1073/pnas.1800756115. Epub 2018 Mar 5) is deemed relevant.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678