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 .
Election/Restrictions
1. The Election filed July 14, 2026 in response to the Office Action of May 15, 2026 is acknowledged and has been entered.
Applicant's election without traverse of Group II, now claims 17-40, and the species of an ion channel, high voltage-activated calcium channel (HVACC), ion channelopathy, and Brugada syndrome is acknowledged. In view of Applicant’s election of and ion channel and HVACC, a voltage-gated calcium channel is included as an elected species. Additionally, in view of the prior art, the diseases are rejoined for examination.
2. Claims 17-40 are pending.
3. Claims 32 and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
4. Claims 17-31, 33 and 35-40 and are currently under consideration as drawn to the elected species.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
5. 37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See ¶¶ 0044 and 0047.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
6. The use of the term(s) nanobody or nanobodies, which are a trade name or a mark used in commerce (see NANOBODY (Ser. No. 85573029, Reg. Date Dec. 13, 2016)), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
7. Claims 17-31, 33 and 35-40 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.
MPEP § 2163 states that 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, 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. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
Scope of the claimed genus
The claims are drawn broadly drawn to a method for treating or ameliorating the effects of a disease in a subject, comprising administering to the subject a chimeric divalent molecule comprising: (a) an E3 ubiquitin ligase binder and (b) a target binder. Thus the claims are broadly drawn to treating with a chimeric divalent molecule comprising a large genus of an E3 ubiquitin ligase binder and a large genus of a target binder. The genus of an E3 ubiquitin ligase binder and the genus of a target binder include subgenera of single domain antibodies. The E3 ubiquitin ligase binder also includes binders that recruit an active Nedd4L to the target or selectively blocks the action of Nedd4L on the target.
State of the Relevant Art
Proteolysis-Targeting Chimeras (PROTACS) that use E3 ligands and a protein targeting domains to direct the ubiquitin proteasome system to a targeted protein for its degradation is known in the art. See Burslem and Crews ( Cell April 2, 2020 181: 102-114, IDS), abstract, pp. 102-103 and Table 1.
As was well-known in the art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required 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”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro & Fransson, (Frontiers in Bioscience 2008; 13:1619-33),see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Additionally, nanobodies are the recombinant variable domains of heavy-chain-only antibodies, which also comprise CDRs 1-3 for binding an antigen. See Sun et al. (Int. J. Nanomedicine 2021, 16:2337-2356), see Abstract and Figs. 1-3.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the structure of the an E3 ubiquitin ligase binder and a target binder, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what a binder with a particular set of functional properties would look like structurally.
Summary of Species disclosed in the original specification
The specification teaches a CaVβ nanobody (βnb). See Example 1-¶ 0044. The specification teaches three nanobodies to the E3 ubiquitin ligase Nedd4L. See Example 1-¶ 0046 and Fig. 4A. The specification does not disclose the structure of the βnb or Nedd4L nanobodies or deposit the nanobodies.
Additionally the specification teaches the current toolbox of small molecule ‘warheads’ that recruit an active E3 ubiquitin ligase are rather limited and further, have not been shown to be effective at targeting multi-pass transmembrane proteins. See Discussion- ¶ [0052]
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that 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.
The specification discloses the reduction to practice of one nanobody to CaVβ and three nanobodies to Nedd4L. The specification does not actually produce any other binders, antibodies, or nanobodies that bind an E3 ubiquitin ligase, an ion channel or a voltage gated calcium channel. E3 ubiquitin ligase or target binders or nanobodies produced by different methods, such as in different species or in phage, or to different epitopes would have been generally expected to be highly structurally diverse, particularly in the CDR sequences. Thus, while applicant has disclosed one nanobody to CaVβ and three nanobodies to Nedd4L, each genus of binder is very large and there is only one species and three disclosed species for each genus. Additionally, the specification does not disclose the structure of the βnb or Nedd4L nanobodies or deposit the antibodies The disclosed species therefore cannot be considered representative of either of the recited genera of binders or nanobodies that bind an E3 ubiquitin ligase, an ion channel, a voltage gated calcium channel, or HVACC. used in the methods recited in the independent claims. See e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that convey the claimed binding activity, a prerequisite for utility in the recited methods of treating.
As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity. But the specification does not describe the CDRs of the nanobodies that confer the binding activity claimed. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for binders or nanobodies that bind an E3 ubiquitin ligase, an ion channel or a voltage gated calcium channel.
For all of the reasons presented above, one of skill in the art would not know which of the countless other antibodies encompassed by the independent claims that meet the highly general structural requirements of the claims would also be able to specifically bind an E3 ubiquitin ligase, an ion channel, a voltage gated calcium channel or HVACC. Neither the specification nor the dependent claims provide sufficient additional structure or a structure/function correlation to provide an adequate written description of the genera claimed. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of antibodies as broadly claimed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claim(s) 17-20, 22, 23, 24, 33, 35, and 36 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0192674 A1 (Wang et al. June 22, 2023, filed May 12, 2021), “Wang”.
Wang teaches the invention relates to a new class of small-molecules having a piperazine or piperidine structure which function as inhibitors of the CaV3.2 voltage gated calcium channel activity (e.g., depolarization-induced calcium influx), and their use as therapeutics for the treatment and/or prevention of CaV3.2 related pain e g., HIV-associated peripheral sensory neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), spinal nerve ligation (SNL) induced neuropathy) and related conditions. See abstract, ¶ 0059 and claims 1 and 10-13.
Wang teaches the present disclosure further provides bifunctional compounds that function to recruit endogenous proteins to an E3 Ubiquitin Ligase for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and/or otherwise inhibited. The description provides methods of using an effective amount of the compounds as described herein for the treatment, prevention and/or amelioration of pain related to CaV3.2 activity, or inhibition of CaV3.2 activity. See ¶ 0026.
Wang teaches the disclosure provides bifunctional or PROTAC compounds, which comprise an E3 Ubiquitin Ligase binding moiety (e.g., a ligand for an E3 Ubiquitin Ligase or “ULM” group), and a moiety that binds a target protein (e.g., a protein/polypeptide targeting ligand or “PTM” group) (e.g., CaV3.2) such that the target protein/polypeptide is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein (e.g., inhibit CaV3.2 activity). In certain embodiments, the PTM is any of the compounds as described herein showing inhibitory activity against CaV3.2 activity. In some embodiments, the ULM is a VHL, cereblon, mouse double minute 2 (MDM2), and/or inhibitor of apoptosis protein (IAP) E3 ligase binding moiety. For example, the structure of the bifunctional compound can be depicted as PTM-ULM. See ¶ 0027.
Regarding claims 20 and 22, Wang teaches targeting molecular components of spinal transmission is a valid therapeutic strategy for the treatment of chronic neuropathic pain. See ¶¶ 0003. Wang teaches The voltage-gated calcium (CaV3.1-3.3) channels constitute the T-type subfamily, whose dysfunctions are associated with epilepsy, psychiatric disorders, and chronic pain. See ¶¶ 0055.
Regarding claim 23, Wang teaches the PTM-ULM compounds can comprise a linker between the PTM and the ULM, i.e. PTM-L-ULM. See ¶¶ 0029-0033.
Regarding claim 24, Wang teaches PTM-ULM compounds recruit endogenous proteins to an E3 Ubiquitin Ligase for degradation, which would be inside a cell. See ¶ 0026.
Claim Rejections - 35 USC § 103
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.
9 Claim(s) 17-31, 33 and 35-40 are rejected under 35 U.S.C. 103 as being unpatentable over Colecraft et al., "Chimeric nanobodies targeting diverse ion channelopathies," 1-2, Columbia Technology Ventures, March 2019, IDS, “Colecraft” in view of Morgenstern et al. (eLife 2019;8:e49253, pp. 1-23, DOI: https://doi.org/10.7554/eLife.49253, IDS) “Morgenstern”.
Colecraft teaches a divalent nanobody system (Diva) targeting NEDD4L regulated plasma membrane proteins to tune their expression levels. Colecraft teaches that the Diva system is comprised of two linked nanobodies one nanobody for targeting the protein of interest and the other targeting NEDD4L to restore or to block NEDD4L mediated ubiquitylation. See p. 1-3rd paragraph.
Colecraft teaches the Diva technology effectively regulates several ion channels implicated in various ion channelopathies. See p. 1-4th paragraph.
Colecraft teaches the Diva system can be used for treatment of ion channelopathies like Long QT syndrome, cystic fibrosis (CFTR), cardiac arrythmias and Parkinson’s disease and for treatment of chronic pain, hypertension and diabetes. See Applications.
Colecraft teaches as set forth above, but does provide an example of administering the diva system for disease treatment or a nanobody targeting a high voltage-activated calcium channel (HVACC), CaV2.2-N-type calcium channel or a CaVb subunit of the HVACC.
Morgenstern teaches isolating an immunized llama nanobody (nb.F3) that binds auxiliary HVACC CaVβ subunits. Nb.F3 by itself is functionally inert, providing a convenient vehicle to target active moieties to CaVβ-associated channels. Nb.F3 fused to the catalytic HECT domain of Nedd4L (CaV-aβlator), an E3 ubiquitin ligase, ablated currents from diverse HVACCs reconstituted in HEK293 cells, and from endogenous CaV1/CaV2 channels, including CaV2.2 channels, in mammalian cardiomyocytes, dorsal root ganglion neurons, and pancreatic β cells. See abstract and Figs. 1-4.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Colecraft and Morgenstern and use the nb.F3 antibody in the divalent nanobody system (Diva) targeting NEDD4L of Colecraft because Colecraft teaches the Diva technology effectively regulates several ion channels implicated in various ion channelopathies and Morgenstern teaches Nb.F3 by itself is functionally inert, providing a convenient vehicle to target active moieties to CaVβ-associated channels, including CaV2.2 channels, to ablate current from the channels. Given the effectiveness of the nb.F3 antibody Morgenstern at targeting CaVβ-associated channels, including CaV2.2 channels, one would have been motivated with a reasonable expectation of success of using the nb.F3 antibody in the divalent nanobody system (Diva) targeting NEDD4L of Colecraft.
Conclusion
10. No claims allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Greg Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER J REDDIG/ Primary Examiner, Art Unit 1646
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