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 .
Status of Claims
On 4/28/26, applicant replied to the 2/3/26 Office action by amending claims 16, 21, 24, and 28. Claims 16-34 are pending and under examination.
Withdrawn Objections and Rejections
The objection to the specification is withdrawn in view of the replacement specification. The objection to claim 16 and the rejections under 35 U.S.C. 112(b) and 112(d) have been overcome by the claim amendments.
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 16-34 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (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. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Claim 16 is drawn to a method of treating or preventing inflammation by administering an antibody specific for a protein antigen capable of binding to nucleic acids or administering an antigen-binding fragment or derivative of the antibody. The antibody, fragment, or derivative also has reduced affinity for Fc[Symbol font/0x67]RIIA and increased affinity for Fc[Symbol font/0x67]RIIB compared with an antibody, fragment, or derivative with the same variable regions but whose constant regions are natural. Claim 16 therefore requires that upon administration, inflammation is reduced or prevented from developing.
Around the time of the invention, skilled artisans recognized the utility of IgG1-based antibodies with increased affinity for Fc[Symbol font/0x67]RIIA and reduced affinity for Fc[Symbol font/0x67]RIIB in treating and preventing inflammation. See, e.g., Chamberlain et al. (US 20060173170) at paragraphs 136 and 140; Lazar et al. (US 20070148171) at paragraphs 189 and 270. Van Vlijmen et al. (US 20060275283) contemplates an antibody with reduced affinity for Fc[Symbol font/0x67]RIIA and increased affinity for Fc[Symbol font/0x67]RIIB but does so in the context of tumor therapy. See paragraphs 155 and 383. Skilled artisans also understood that Fc[Symbol font/0x67]RIIA and Fc[Symbol font/0x67]RIIB are distinct subunits of FC[Symbol font/0x67]RII receptor (CD32) that have different cellular effects upon activation. (See Koenig et al., US 20200131265, at paragraphs 9-11.) They would therefore not have understood these antibodies as being interchangeable for each other in the context of the claimed function.
Skilled artisans were also aware of antibodies that bind influenza proteins and have differential affinity for Fc[Symbol font/0x67]RIIA and Fc[Symbol font/0x67]RIIB; see Bourzanos et al. (2020, Nature 588: 485-514; NPL reference 2 on 4-page IDS of 12/11/23) at Figure 1. These antibodies, however, bind the hemagglutinin coat protein of influenza virus, not one of its nucleic-acid-binding proteins. (Figure 1b.) Mimoto et al. (Protein Engineering: Design and Selection 26: 589-598; NPL reference 30 on 8-page information disclosure statement of 12/11/23) describes an antibody with enhanced FC[Symbol font/0x67]RIIb binding over binding to certain mutants of FC[Symbol font/0x67]RIIa relative to wild-type IgG1 but does not link that antibody to any function in inflammatory processes. The skilled artisan considering the claimed invention in view of the prior art, therefore, would not have been able to make and use antibodies with the claimed binding profile that treat or prevent inflammation without undue experimentation.
The as-filed disclosure fails to provide evidence that the skilled artisan would have expected success in treating or preventing inflammation in a subject by providing an antibody with reduced affinity for Fc[Symbol font/0x67]RIIA and/or increased affinity for Fc[Symbol font/0x67]RIIB in particular. The specification actually does not disclose any antibodies with this property. The working examples are confined to investigations of an antibody that binds nucleoproteins yet does not bind Fc[Symbol font/0x67]R receptors; this antibody induces an inflammatory response in human PBMCs (peripheral blood mononuclear cells). (See, e.g., Example 3 starting at page 24.) Specifically, Example 3 teaches that an antibody with E233P F234V L235A D265A mutations (see claim 25) lacks Fc[Symbol font/0x67]R effector activity. The disclosure speculates that a person of ordinary skill in the art will be able to generate antibodies with Fc domain modified “so as not to bind Fc[Symbol font/0x67]RIIA . . . or even to preferentially bind to Fc[Symbol font/0x67]RIIB,” but there is no evidence in the specification that such antibodies would have been expected to reduce or prevent inflammation upon administration to a subject. (See page 19, lines 26-29.)
While a singular, narrow working embodiment cannot be a sole factor in determining enablement, its limited showing, in light of the unpredictable nature of the art and the lack of direction applicants present, provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have a reasonable expectation of success in using the claimed invention without undue experimentation.
Claims 16-34 remain 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.
M.P.E.P. § 2163 recites, “An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. . . . One must define a compound by ‘whatever characteristics sufficiently distinguish it.’ A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process.”
Claim 16 recites “an antibody specific for a protein antigen capable of binding to nucleic acids”—i.e., any antigen capable of binding to any nucleic acid—that “has a reduced FC[Symbol font/0x67]RIIA-receptor binding capacity and/or an increased Fc[Symbol font/0x67]RIIB-receptor binding capacity” compared with an antibody, fragment, or derivative with the same variable regions but whose constant regions are natural and that treats or prevents inflammation in a subject upon administration. The as-filed disclosure is insufficient for the skilled artisan to conclude that applicants possessed an antibody with these functions. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2164(I)(A). Such is the case here.
The art around the time of the invention discloses no structure-function correlation for antibodies that bind nucleic-acid-binding proteins, treat or prevent inflammation, and have the required differential affinities for Fc[Symbol font/0x67]RII receptor subunits. The art recognized IgG1-based antibodies with increased affinity for Fc[Symbol font/0x67]RIIA and reduced affinity for Fc[Symbol font/0x67]RIIB in treating and preventing inflammation. See, e.g., Chamberlain et al. (US 20060173170) at paragraphs 136 and 140; Lazar et al. (US 20070148171) at paragraphs 189 and 270. Van Vlijmen et al. (US 20060275283) contemplates an antibody with reduced affinity for Fc[Symbol font/0x67]RIIA and increased affinity for Fc[Symbol font/0x67]RIIB but does so in the context of tumor therapy and does not reduce the antibody to practice. See paragraphs 155 and 383.
Skilled artisans were also aware of antibodies that bind influenza proteins and have differential affinity for Fc[Symbol font/0x67]RIIA and Fc[Symbol font/0x67]RIIB; see Bourzanos et al. (2020, Nature 588: 485-514; NPL reference 2 on 4-page IDS of 12/11/23) at Figure 1. These antibodies, however, bind the hemagglutinin coat protein of influenza virus, not one of its nucleic-acid-binding proteins. (Figure 1b.) Mimoto et al. (Protein Engineering: Design and Selection 26: 589-598; NPL reference 30 on 8-page information disclosure statement of 12/11/23) describes an antibody with enhanced FC[Symbol font/0x67]RIIb binding over binding to certain mutants of FC[Symbol font/0x67]RIIa relative to wild-type IgG1 but does not link that antibody to any function in inflammatory processes.
The prior and contemporaneous art does not provide a correlation between an ability to treat/prevent inflammation, bind a nucleic-acid-binding protein, and exhibit reduced Fc[Symbol font/0x67]RIIA binding and increased Fc[Symbol font/0x67]RIIB binding. The as-filed disclosure does not teach such a correlation either. There is no reduction to practice of any antibody with the claimed functions and no teachings on what the structure of such an antibody might be. Applicant has not provided a number of species that represents the claimed genus, and the disclosure is therefore inadequate to meet the written-description requirement. See MPEP 2163 (II)(A)(3)(a)(ii).
The disclosure speculates that a person of ordinary skill in the art will be able to generate antibodies with Fc domain modified “so as not to bind Fc[Symbol font/0x67]RIIA . . . or even to preferentially bind to Fc[Symbol font/0x67]RIIB,” but even if this were the case, it would not meet the written-description requirement for a demonstration of possession. (See specification at page 19, lines 26-29.) The enablement requirement and written-description requirement are separate from each other.
Response to Arguments
Regarding the enablement rejection, applicant alleges that “[n]umerous antibodies with a reduced binding capacity to the Fc[Symbol font/0x67]RIIA receptor and/or an increased binding capacity to the Fc[Symbol font/0x67]RIIB receptor were already well known at the priority date of the invention, . . . as explained in detail in the description.” (Remarks at 10.) Applicant then points to various portions of the specification as allegedly teaching these antibodies. These remarks are not understood. For example, applicant alleges that page 11, lines 34-36, teaches “antibody fragments or derivatives without an Fc domain.” Page 11, lines 34-36, of the as-filed specification reads:
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Page 11, lines 34-36, discusses reduced Fc[Symbol font/0x67]R binding due to certain point mutations in IgG2, not fragments/derivatives that lack an Fc domain. The discussion at pages 10-11 of the remarks is inconsistent with the as-filed specification, the replacement specification, and the marked-up specification, so the examiner cannot evaluate these statements.
Applicant alleges that “antibodies with the Fc receptor binding capacities recited in claim 16” “were already well known.” (Reply at 11.) The basis for this statement is unclear. Applicant has not identified by name any prior-art reference that teaches antibodies with increased affinity for Fc[Symbol font/0x67]RIIA and reduced affinity for Fc[Symbol font/0x67]RIIB. “Arguments presented by the applicant cannot take the place of evidence in the record.” MPEP 716.01(c). Furthermore, applicant has not explained why the skilled artisan would have known how to use those antibodies in the treatment of inflammation. Van Vlijmen (cited above and previously) contemplates an antibody with reduced affinity for Fc[Symbol font/0x67]RIIA and increased affinity for Fc[Symbol font/0x67]RIIB but does so in the context of tumor therapy, not treating inflammation.
Applicant refers to experimental data in examples 1 and 2 as providing an enabling disclosure. Among other things, applicant alleges that “Fab fragments without an Fc are known in the art to have reduced binding capacity to the Fc[Symbol font/0x67]RIIA receptor” and that antibodies having an Fc fragment mutated by four particular mutations “are known in the art to have reduced binding capacity to all activating Fc[Symbol font/0x67]R and thus notably to the Fc[Symbol font/0x67]RIIA receptor.” (Reply at 12-13.) There is no evidence proffered to support either of these statements about what was allegedly known in the art before the effective filing date. “Arguments presented by the applicant cannot take the place of evidence in the record.” MPEP 716.01(c).
Applicant highlights Examples 1 and 2 as demonstrating that some immune complexes (ICs) induce an inflammatory reaction (as measured by IL-6 secretion by human PBMCs), with ICs lacking an Fc region not stimulating inflammation. (Reply at 13, citing Example 5 at page 34, lines 3-18, and Figure 5.) Example 5 compares the inflammatory effect of Ncp (SARS-CoV-2 nucleocapsid protein), free Fab-aNcp15 antibody, a complex of Ncp with hcaNcp15 antibody (human constant region, mutated variable region; page 32, lines 18-22), and a complex of Ncp with Fab-aNcp15 antibody. Figure 5 shows that of these four, only Ncp/hcaNcp15 stimulates IL-6 secretion from PBMCs:
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Example 5 goes on to conclude that “IL-6 secretion cannot be caused by an immune complex containing a Fab.” While this point is not in dispute as far as Figure 5 goes, the fact that an antibody or complex does not stimulate IL-6 does not necessarily mean it will be therapeutic for inflammation. Upon administration, it may simply not contribute to IL-6-mediated inflammation already in progress. There are no working examples in which inflamed PBMCs are contacted with any antibody and reduced inflammation is observed, for example. Furthermore, applicant has not explained how the antibodies of Example 5 have reduced Fc[Symbol font/0x67]RIIA-binding capacity and increased Fc[Symbol font/0x67]RII binding capacity. Applicant bears the burden of explaining data proffered as evidence; MPEP 716.02(b). Attorney argument is not evidence; MPEP 716.01(c).
Applicant also points to Example 6 as showing that “the inflammatory reaction induced by ICs with a wild-type Fc fragment is blocked by an Ncp-specific Fab.” (Page 12, citing Example 6 and Figure 7.) Again, however, the fact that an antibody or complex does not stimulate IL-6 does not necessarily mean it will be therapeutic for inflammation. Applicant has also not explained how the antibodies of Example 6 have reduced Fc[Symbol font/0x67]RIIA-binding capacity and increased Fc[Symbol font/0x67]RII binding capacity. Applicant bears the burden of explaining data proffered as evidence; see MPEP 716.02(b). Attorney argument is not evidence; MPEP 716.01(c).
Regarding the written-description rejection, applicant reiterates that the working examples show that “an inflammatory reaction can be induced in vitro by ICs containing the HIV-1 transcriptional transactivator (Tat) or the SARS-CoV-2 nucleocapsid protein (Ncp),” which bind nucleic acids. (Reply at 13-14.) As an initial matter, these antibodies and complexes represent only two investigated species, but the cited prior art makes clear that the genus of antibodies, fragments, and derivatives with the claimed properties is unpredictable. “[W]hen there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.” MPEP 2163(II)(A)(3)(a)(ii). This standard has not clearly been met.
Applicant repeats the explanations of Examples 5 and 6 already made regarding enablement. (Reply at 14.) As discussed above, it is not clear that antibodies or complexes that fail to induce IL-6 secretion are necessarily anti-inflammatory when inflammation is already taking place, as would be required for a method of treating inflammation. There is also no evidence that, for example, when the antibodies or complexes are added to PBMCs followed by a proinflammatory cytokine, the antibodies or complexes would prevent that cytokine from stimulating inflammation.
Applicant’s reply includes a request for an interview. (Reply at 15.) Due to intra-Office deadlines, however, the examiner is unable to accommodate applicants once examination of the reply has commenced. Future requests for interviews should comply fully with 37 CFR 1.4(c), which requires that each distinct inquiry be contained in a separate paper. The Automated Interview Request form located in Patent Center may be used to request an interview. See https://www.uspto.gov/patents/laws/interview-practice. In the alternative, applicants may contact the examiner by telephone to arrange a mutually convenient time.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the modification to the grounds 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LORA E BARNHART DRISCOLL, whose telephone number is (571)272-1928. The examiner can normally be reached M-F 7:00-4:00 p.m. ET.
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, Patricia Engle, can be reached at 571-272-6660. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Lora E Barnhart Driscoll/ Primary Examiner, Art Unit 3991
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