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 .
Election/Restrictions
Applicant’s election without traverse of Group 1, with species elections to allosteric site, agonist, azobenzene, glutamate receptor, metabotropic glutamate receptor, and nanobody in the reply filed on September 2, 2022 is acknowledged. Upon search and reconsideration, the claims have been examined in their entirety.
Claims 56-61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/11/2024.
Claims 1, 8, 13 and 62 and 63 are under consideration in the instant Office Action.
Modified Rejections Necessitated by Amendment
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.
Claims 1, 8, 13 and 62-63 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
Newly amended claim 1 now requires that the conjugate is configured to attach to the metabotropic glutamate receptor solely via binding of the affinity agent to the metabotropic glutamate receptor. This new limitation now requires a very specific function without any specific structure requirements. While the affinity agent is an antibody that binds to a metabotropic glutamate receptor as set forth in claim 1, there is no clear structure requirement of how to achieve the requirement of how the antibody attaches to the metabotropic glutamate receptor solely via binding of the affinity agent to the metabotropic glutamate receptor. There is no description in the instant specification that indicates how to achieve this sole binding of the metabotropic glutamate receptor with an affinity agent. A metabotropic glutamate receptor is a general term that encompasses many possible metabotropic glutamate receptors that include mGluR1-mGluR8. Newly amended claim 1 now calls for selecting the metabotropic glutamate receptors from mGluR2-4 and mGluR6-8. While the new limitations of metabotropic glutamate receptors from mGluR2-4 and mGluR6-8 is narrower in scope it is still a very broad genus without a specific structure for what is being bound. Without specific guidance, it is unclear which specific metabotropic glutamate receptor binding antibody will support the minimum structure necessary for the new limitation of solely binding the affinity agent to the metabotropic glutamate receptors. It is also pointed out that this is still a very large genus of potential antibodies which are not all known and therefore, read on any potentially new and undiscovered antibodies that may or may not meet the newly required limitation since the metabotropic glutamate receptors themselves are a broad genus of targets, themselves. Claim 62 calls out specific nanobodies, NB-8260, NB-8236 and NB-8243, that bind metabotropic glutamate receptors but there are issues with this disclosure since the prior art and the instant specification fail to provide any structure for these nanobodies. The only mention of these nanobodies is only found in [096] of the instant specification which describes nanobodies in general and [0348] where in the named nanobodies are mentioned but no structure is provided for these antibodies.
Further, claim 1 requires a “ligand” that binds to a metabotropic glutamate receptor, claim 8 requires the ligand binds at an allosteric site or at an orthosteric site and claim 13 requires the ligand is an agonist, an antagonist, an allosteric modulator, or a blocker. All of requirements are functions for a ligand and does not require any specific structure. Therefore, the term “ligand’ is not limited to any specific genus and can have any function as set forth in instant claim 13. Again the instant specification fails to make up for the deficiencies of the what is required in a structure for the claimed “ligand”. The instant specification at [090] and [0123-124] define ligands as molecules that include small molecules, peptide, proteins that bind to a polypeptide and effects a change. This definition encompasses a tremendous breath of potential genera and structures. The term “ligand’ is disclosed to encompass naturally-occurring ligands and synthetic ligand and can be an agonist, antagonist, an allosteric modulator or blocker. There is no limit to what is encompassed by the term “ligand” in the instant specification and the instant claims only require that the ligand bind metabotropic glutamate receptors. Therefore, there is no structure/function correlation for the term “ligand” and there is no written description support for the term “ligand” to inform the public of the metes and bounds for this term.
As detailed below, applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genera, and as such, applicant’s disclosure does not satisfy the written description requirement of 30 U.S.C. 112(a).
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions (CDRs) that provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see Almagro et al, 2008, Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1; 1/15/2025 PTO-892).
Even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg 11).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genera of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Further, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs and a nanobody is a single variable domain (VHH, aka single-domain antibody (sdAb)) only requiring the three CDRs from the one of the variable chain regions. Sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention comprises new antibodies, or at the least disclosure of new antibodies that could not have been envisaged from the prior art, which indicates that the prior art was not in possession of all the antibodies that attached solely via the binding of the affinity agent to the glutamate receptor as claimed.
In Williamson v. Citrix Online, LLC, 792 F.3d 1339, 1349, 115 USPQ2d 1105, 1111 (Fed. Cir. 2015) the court stated: “[t]he standard is whether the words of the claim are understood by persons of ordinary skill in the art to have a sufficiently definite meaning as the name for structure” (MPEP 2181). The ordinary artisan would not have understood that the applicant was in possession of only a finite number of antibodies and would not be able to envision the genera conjugates with an affinity agent that attached solely via the binding of the affinity agent to the glutamate receptor as claimed. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
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., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic or generic ligand that binds a metabotropic glutamate receptor, such as antibody that binds a metabotropic glutamate receptor, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody or the ligand to demonstrate possession of the breadth of the genus of antibodies or ligands that bind a metabotropic glutamate receptor via solely the affinity agent as encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (1/15/2025 PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies or ligands because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding and the great breath of what is encompassed by the term “ligand”.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of an antibody that binds a metabotropic glutamate receptor via solely the affinity agent or a ligand that binds a metabotropic glutamate receptor. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
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. 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.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope and a generic ligand that bind to a metabotropic glutamate receptor. The specification does not provide a consistent structure for all of the possible antibodies or ligands and fails to provide a representative number of species for the claimed genus for these two limitations. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
See MPEP 2181.IV, which states: “The Federal Circuit has recognized the problem of providing a sufficient disclosure for functional claiming, particularly with generic claim language, explaining that "The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the applicant [inventor] has made a generic invention that achieves the claimed result and do so by showing that the applicant [inventor] has invented species sufficient to support a claim to the functionally-defined genus." Ariad Pharmaceuticals Inc. v. Eli & Lilly Co., 598 F.3d 1336, 1349, 94 USPQ2d 1161, 1171 (Fed. Cir. 2010) (en banc).”
As already discussed above, the specification does not provide adequate written description for the entire claimed genera for the antibodies or ligands, because one skilled in the art would be unable to immediately envision, recognize, or distinguish most of the members comprised within the genera claimed, specifically which antibodies should be used in the claimed conjugate with the required function or the plethora of possible ligands.
Therefore, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies or ligands of the claimed conjugate product, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1, 8, 13, 18-19 and new claim 62-63 do not meet the written description requirement.
Response to Arguments
Applicant's arguments filed 9/2/2025 have been fully considered but they are not persuasive. Applicant argues that the new limitation of nanobodies of metabotropic glutamate receptors overcomes the written description requirement because the nanobody is towards a single variable domain (VHH, aka single-domain antibody (sdAb)) and is not an antibody itself and therefore, the written description requirements for an antibody does not apply. This is an incorrect statement. A single-domain antibody (sdAb), also known as a nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight of only 12–15 kDa, single-domain antibodies (sdAbs) are much smaller than common antibodies (150–160 kDa) which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments (~50 kDa, one light chain and half a heavy chain) and single-chain variable fragments (~25 kDa, two variable domains, one from a light and one from a heavy chain; see Wikipedia , downloaded 11/17/2025, Instant PTO-892). Therefore, while nanobodies are specialized antibodies, they are still part of the antibody genus and still have the same issues as other types of antibodies. The biggest difference is that the single-domain antibody (sdAb) only requires three CDRs rather than the usual six CDRs. sdAb still require a structure function correlation and require specific CDRs when these nanobodies require a specific function and calling out their epitope, either in generic terms or specific amino acid sequences, does not meet the written description requirement. Therefore applicant’s arguments or newly amended claims do not overcome the written description rejection set forth above.
As previously addressed, the limitation of a metabotropic glutamate receptors narrow the scope, the instant claims still encompasses an enormous breath of potential antibodies or nanobodies and so forth. Further, while the art does teach antibodies against metabotropic glutamate receptors, there is no evidence provided that these are all of the possible antibodies that are encompassed by the enormous breath of the claimed genera of a metabotropic glutamate receptor binding antibodies. As already shown by Edwards et al., 2003 (1/15/2025 PTO-892) which teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). This shows that antibodies against a large number of metabotropic glutamate receptors and all of the potential epitopes from these proteins reads on incalculable amount of possible antibodies encompassed by the antibodies against a metabotropic glutamate receptor that is not covered by what is known in the prior art.
Therefore, the new amendments have not overcome the written description rejection as set forth above.
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.
Claim 1, 8, 13, and 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 11-15, of U.S. Patent No. 12,076,329. Although the claims at issue are not identical, they are not patentably distinct from each other because ‘329 claims a conjugate with the components requiring an affinity agent that is a nanobody that binds to metabotropic glutamate receptors, photoisomerizable regulators which comprise azobenzene and ligand that binds to glutamate. Therefore, ‘329’s claimed invention anticipates the instant claims.
Response to Arguments
Applicant's arguments filed 9/2/2025 have been fully considered but they are not persuasive. Applicant argues that the new amendments now requiring nanobodies and photoisomerizable regulators are not taught by the ‘326 patent. This is not found persuasive since these limitations are present in the ‘329 claims and teach the genus of the claimed species which are obvious variants of the ‘329 claims. Therefore, the arguments are not found persuasive and the rejection is maintained.
Conclusion
No claims are allowed.
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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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675