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 1, 3-15, 17-21, 24, 29-31, 33-39, 51, and 54 are pending and under consideration.
Specification
The disclosure is objected to because of the following informalities: The specification filed 04/12/2024 is objected to for recitation of amino acid sequences in the absence of a sequence identifier. See for example, pages 2, 5, 23-26, 28-29 etc. See 37 CFR 1.821(c). 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825.
The disclosure is further objected to because of the following informalities: The brief description of the drawings has several references to colored items. For example, the specification teaches:
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Also see descriptions of Figure 1 where it states, “color coding is as in” and Figure 5, etc. Thus, it appears that some of applicants’ drawings may need to be submitted in color to distinguish these details. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Applicants are reminded that color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 34-36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 34-36 are rejected to as indefinite for reference to Table 4. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP 2173.05, “Specific Topics Related to Issues Under 35 U.S.C. 112(b)”
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.
Claim(s) 1, 3-15, 17-21, 24, 29-31, 33-39, 51, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Rujas et al. (BioRxiv, October 16, 2020) in view of Svilenov et al. (BioRxiv, December 11, 2020), Lonberg et al. (US 20200299400, 05-24-2018), and Chiu et al. (US 20190062420, 08-24-2018)
(Briefly- Svilenov et al. appears to teach every aspect of Claim 1 except the IgG4 Fc and it’s mutations chain.)
Regarding claims 1, 37-38, 51, Rujas et al. teach a self-assembled polypeptide complex comprising the light chain of human apoferritin wherein the N-terminus of each apoferritin subunit points outwards of the spherical nanocage and is therefore accessible for the genetic fusion of proteins of interest. Upon folding, apoferritin protomers act as building blocks that drive the multimerization of the 24 proteins fused to their N termini. The reference further teaches construction of a single-chain Fab (scFab) and Fc (scFc) polypeptide constructs to allow for their direct fusion to the N terminus of the apoferritin protomer. This reads on “one or more fusion proteins comprising a nanocage monomer or subunit thereof linked to an Fc polypeptide”. See Figure 1A below:
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The reference further teaches, “We used the self-assembly of the light chain of human apoferritin to multimerize antigen binding moieties targeting the SARS-CoV-2 S glycoprotein.”. This encompasses part (b) of claim 1 wherein one or more fusion proteins comprising a nanocage monomer or subunit thereof is linked to a SARS-COV-2 binding moiety.
Regarding Claims 15 and 17, as set forth above, the nanocage monomer or subunit thereof is a human ferritin or subunit thereof.
Regarding Claims 18-19, Rujas et al. teach that based on its four-helical bundle fold, the human apoferritin protomer was split into two halves: the two N-terminal α helices (N-Ferritin) and the two C-terminal α helices (C-Ferritin). Thus, the ferritin monomer subunit is a C-half ferritin (also see Figure 1A).
Regarding claims 20-21, Rujas et al. teach, constructing a single-chain Fab (scFab) and Fc (scFc) polypeptide constructs to allow for their direct fusion to the N terminus of the apoferritin protomer with the inclusion of a linker (see Figure 2A).
Regarding claims 24, and 37-39; Rujas et al. teach that based on its four-helical bundle fold, the human apoferritin protomer was split into two halves: the two N-terminal α helices (N-Ferritin) and the two C-terminal α helices (C-Ferritin). In this configuration, the scFc fragment of human IgG1 and the scFab of anti-SARS-CoV-2 IgGs were genetically fused (via linkers) at the N terminus of each apoferritin half, respectively. Split apoferritin complementation led to hetero-dimerization of the two halves and in turn, full apoferritin self-assembly displaying more than 24 copies of scFc and scFab on the nanocage periphery. Absent evidence to the contrary, this structure (also see Figure 2A of Rujas et al.) appears to encompass the self-assembled polypeptide complex wherein the Fc polypeptide comprises a single chain Fc (scFc) comprising two Fc chains, wherein the two Fc chains are linked via an amino acid linker.
Regarding claims 29-31, Rujas et al. teach that the SARC-COV-2 binding moiety comprises an antibody or antibody fragment, including an Fab fragment- “ We demonstrate the ability of this technology to combine one to three different Fab specificities together with Fc on the same molecule.”. “Because a Fab is a hetero-dimer consisting of a light and a heavy chain, and the Fc is a homodimer, we created single-chain Fab (scFab) and Fc (scFc) polypeptide constructs to allow for their direct fusion to the N terminus of the apoferritin protomer.”. “The modularity and flexibility of the platform was exemplified by enhancing the potency of a VHH and multiple Fabs that target non-overlapping regions on two SARS-CoV-2 S sub-domains.”
Regarding claim 33, Rujas et al. teach that the light chain of human apoferritin displaying 24 copies of VHH-72 assembled into monodisperse, well-formed spherical particles (Fig. 1b-c) and showed an enhanced binding avidity to the S protein. Rujas et al. further teach, SARS-CoV-2 PsV neutralization assays with the split design multabodies (MBs) showed that enhanced binding affinity for the S protein translates into an improved neutralization potency in comparison to their IgG counterparts, with a ~1600-fold and ~2500-fold increase for BD23 and A48, respectively.
Regarding Claims 34-36, Rujas et al. teach (Figure 5) that the SARS-CoV-2 binding moiety comprises a single chain variable domain comprising a variable domain from monoclonal antibodies 298, 324, 46, 80, 52, 82, or 236. See also the 298-80-52 multabody cocktail in Figure 8S.
Rujas et al. teach as set forth above, but, in regard to claim 1, Rujas et al.’s Fc polypeptide comprised IgG1 whereas Claim 1 is specific to “an IgG4 Fc chain”. Rujas et al. also do not teach any of the claimed IgG4 mutations as set forth in claims 3-14.
Svilenov et al. teaches (abstract) that severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) enters its host cells after binding to the angiotensin-converting enzyme 2 (ACE2) via its spike glycoprotein. A concern arising from the experience with vaccines and neutralizing antibodies is disease enhancement by Fc effector functions (see introduction, 4th para) such as complement dependent cytotoxicity (CDC) and antibody dependent cytotoxicity (ADCC). Fusion of the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain can prolong the in vivo half-life but bears the risk of unwanted Fc-receptor activation and antibody-dependent disease enhancement. The authors describe optimized ACE2-Fc fusion constructs that avoid Fc-receptor binding by using IgG4-Fc as a fusion partner. They further teach that it is well known that IgG1-Fc strongly binds to CD16 and has pronounced CDC and ADCC activity, whereas in contrast for IgG4-Fc such Fc-related effector functions are minimal. For this reason, the IgG4-Fc fragment would be a preferred fusion partner for ACE2.
Lonberg et al. also teaches [0264] use of IgG4 or portions thereof where effector function is to be avoided altogether, and effector function only leads to (or increases the risk of) undesired side effects. The reference further teaches [0267-0268] well-known Fc modifications for reducing effector functions in IgG4 such as L235A, F234A, G237A, and S228P.
Chiu et al. teaches [0123] additional well-known IgG4 Fc mutations for reducing effector functions. For example, Chiu et al. teach that exemplary mutations that may be made singularly or in combination are mutations K214T, E233P, L234V, L234A, deletion of G236, V234A, F234A, L235A, G237A, P238A, P238S, D265A, S267E, H268A, H268Q, Q268A, N297A, A327Q, P329A, D270A, Q295A, V309L, A327S, L328F, A330S and P331S in IgG1, IgG2, IgG3 or IgG4. The reference also specifically teaches combining some of the specific IgG4 FC mutations such as: S228P/F234A/L235A/G237A/P238S or S228P/F234A/L235A or F234A/L235A.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have exchanged the IgG1 Fc chain of Rujas et al. with an IgG4 Fc chain for the purposes of treating or preventing SARS-Cov-2 in a subject because, in constructing a vaccine against SARS-COv-2, Svilenov et al. taught that one should use the IgG4 Fc chain as it was well known that IgG1-Fc has pronounced complement dependent cytotoxicity (CDC) and antibody dependent cytotoxicity activity (ADCC). In contrast, IgG4 Fc-related effector functions are minimal. Lonberg et al. also teaches [0264] use of IgG4 or portions thereof where effector function is to be avoided altogether, and effector function only leads to (or increases the risk of) undesired side effects. One would have been motivated to do so, because when treating a subject with vaccines and neutralizing antibodies, the ordinary artisan would want to minimize disease enhancement by Fc effector functions. Further, regarding claims 3-14, it would have been further obvious for one of ordinary skill in the art to select any one of more of amino acid positions 228, 234, 235, 237, and 238 for modification because such modifications were well-known to promote reduced effector functions. Each mutation (i.e., S228P, F234A, L235A, G237A and P238S) was individually taught in the prior art or taught as combinations for the purposes of reducing an Fc-related effector function (see Lonberg et al. and Chiu et al.).
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, 3-15, 17-21, 29-31, 33-39, 51 and 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-10, 11-12, 21-23, 26-28, 30, 32, 35-39, 41, 45-50, 67-70, 100, and 103 of copending Application No. 18/030944 (‘944, reference application) in further view of Lonberg et al. (US 20200299400, 05-24-2018), and Chiu et al. (US 20190062420, 08-24-2018).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application either overlap in scope or are obvious variations of the currently claimed invention. For example, Claim 1 of the current application is drawn to:
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This overlaps in scope with the following claims from the ‘944 application:
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as the reference application teaches [0212] that the Fc fragment may be derived from any type of antibody and defines the antibodies [0177] as inclusive of IgA, IgD, IgE, IgG, such as IgG1, IgG2, IgG3, and IgG4, and IgM.
Currently examined dependent claims 15, and 17-18 further define the nanocage monomer as a “ferritin monomer or subunit thereof”, and a “human ferritin”. The specification of the current application states [0194] that the terms “ferritin” and “apoferritin” are used interchangeably. Hence, this compares in scope to the reference claims 68-70 and claims 21-22 drawn to:
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Claim 23 of the reference application is drawn to:
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This appears to encompass or overlap with Claims 19 and 20 of the current application.
Regarding currently examined claim inclusive of linkers, this overlaps in scope with ‘944 claims 26-28, 28, and 30. The current specification teaches [0244] that the definition of linkers are inclusive of GGS repeats.
Regarding currently examined claims 29-31 wherein the SARS-CoV-2 binding moiety comprises an antibody, a Fab fragment or comprises a scFab, scFv, a sdAb or VHH; this overlaps in scope with reference application claims 4-7.
Regarding current examined claims 33-36 (inclusive of specific SARC-CoV-2 monoclonal antibodies), such claims overlap in scope with reference claims 2 (targeting the S (spike) glycoprotein), 8, 9, 10, 35, 36, 37, 38, 39, 45-46, and 103.
Regarding currently examined claims 37-39, drawn to:
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Such claims are obvious variations or overlap in scope with reference claims 11-12. Furthermore, reference claims 47-49 are drawn to nucleic acids, vectors, and host cells which would be obvious to include in the current claims because one would ordinarily make the fusion constructs with such starting materials.
Further, regarding pending claims 3-15, it would be obvious to one of ordinary skill in the art at the time of filing to modify the Fc region (and thus include the known mutations) to reduce effector functions as taught by Lonberg et al. (US 20200299400, 05-24-2018), and Chiu et al. (US 20190062420, 08-24-2018). One of ordinary skill in the art would have selected any one of more of amino acid positions 228, 234, 235, 237, and 238 for modification because such modifications were well-known to promote reduced effector functions. Each mutation (i.e., S228P, F234A, L235A, G237A and P238S) was individually taught in the prior art or taught as combinations for the purposes of reducing an Fc-related effector function.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643
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