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 .
Specification
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The specification is objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)).
Drawings
The drawings are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)). The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.” Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation “FIG.” must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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, 3-14, 16-17, 21, 23, 27, 29, and 31-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The 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 inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[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.' (internal quotation marks omitted).").
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
Instant claims 1, 3-14, 16-17, 21, 23, 27, 29, and 31-32 broadly encompasses an immunogenic composition comprising at least one isolated influenza HA stem polypeptide. An immunogenic composition inherently requires the function of immune stimulation/modulation.
Instant claim 17 further recites that the isolated influenza HA stem polypeptide has at least 90% identity, 95% identity, 98% identity, or 99% identity with SEQ ID NOs 1-4.
The Specification defines an ‘isolated influenza HA stem polypeptide’ a polypeptide comprising a full-length influenza HA stem region or an immunogenic fragment or variant of an influenza HA stem region.
The Specification has failed to sufficiently describe the structural features that must be retained by the members of the claimed genus as to establish a structure-function relationship with respect to the vaccine and immune stimulation.
“[A]t least one isolated influenza HA stem polypeptide” encompasses a large pool of variant polypeptides when accounting for immunogenic fragments and variants and the Specification does not adequately describe the necessary epitope that must remain for the fragments and variants to be immunogenic.
An amino acid sequence having at least 90% identity with SEQ ID NOs: 1-4 encompasses a large pool of variant polypeptides when allowing for changes of up to 10% of the amino acid residues.
While the instant claims are drawn to a genus that comprises innumerable permutations of sequences and HA stem polypeptides, the Specification has only adequately described and successfully reduced to practice specific sequences/HA stem polypeptides, SEQ ID NOs: 1-4, 6-9, and 13-16. As such, the Specification reasonably demonstrates that Applicant was in possession of vaccine compositions consisting of SEQ ID NOs: 1-4, 6-9, and 13-16. However, this is not representative of the extremely large genus of sequences/HA stem polypeptides claimed since these sequences only encompass 4 flu strains and not the innumerable sequences contained within a genus of sequences comprising up to 10% of amino acid substitutions and within a genus of HA stem polypeptides comprising the innumerable fragments and variants thereof.
The data generated for SEQ ID NOs: 1-4, 6-9, and 13-16 described in the Specification cannot reasonably be extrapolated and applied to support possession of the entire claimed genus of variants and fragments because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials consisting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1966).
Gomez Lorenzo, et al. (Chest. 2013 Feb 1;143(2):502-510., hereinafter “Gomez Lorenzo”) provides a review of the state of the art in influenza HA stem vaccines. Influenza vaccine that use the HA stem region do not use portions of this region, rather the intact HA stem region is used (Steps Toward Development of a Universal Influenza Vaccine, pg. 505 column 2). While Applicant may have described fragments or variants of these proteins, as the fragments/variants have not been shown to be immunogenic, these fragments would not reasonably be considered an immunogenic composition.
Accordingly, the claims as currently written are not adequately described and one of skill in the art would readily appreciate that Applicant was not in possession of the claimed genus at the time of filing.
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 16-17 and 23 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.
Claim 16 is drawn to a composition, but the claim language includes method and use claims which are not compositions. Use claims are not allowed as well as method claims dependent on composition claims. Deletion of the phrase “or use or method” would fix the stated issue.
Claim 16 recites the limitation "the linker" in line 2. There is insufficient antecedent basis for this limitation in the claim because the linker is not previously mentioned in claims 1, 6, or 16.
The phrase “an amino acid sequence” in claim 17 is indefinite. The phrase is not defined in the claim or specification. One of ordinary skill would not be able to reasonably ascertain the invention. For example, “A sequence that is at least 90% identical” may include sequences 10 residues long with 9/10 residues being identical to the claimed sequence. “[The] sequence” is the appropriate terminology which would fix the indefiniteness of the claims.
Claim 23 recites the broad recitation at least 0.4 mg, and the claim also recites 0.4 to 9.5 mg which is the narrower statement of the range/limitation. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claims 1, 3-4, 6-14,16-18, 21, 23, 27, 29, and 31 are rejected under 35 U.S.C. 102 (a)(1) and a(2) as being anticipated by Nabel, et al. (WO 2019/195284 A1, FOR-IDS, filed, 09/22/2023, hereinafter “Nabel”).
Regarding claim 1, Nabel discloses a vaccine comprising an isolated HA stem polypeptide and the AF03 (squalene based) adjuvant (¶0061 and Figure 25A-C).
Regarding claim 3, Nabel discloses administering the HA stem polypeptide and adjuvant vaccine to Cynomolgus Macaques to elicit an immune response (¶0061 and Figure 25A-C).
Regarding claim 4, Nabel discloses that the stem polypeptides are engineered stabilized stem antigens (¶0028).
Regarding claims 6-10, Nabel discloses that the HA stem polypeptide is presented on a ferritin nanoparticle, where the ferritin is H. pylori ferritin or Trichoplusia ferritin (¶0068, ¶0071, ¶0053).
Regarding claims 11-12, Nabel discloses that the composition is composed of two different Influenza A proteins, selected from H1, H3, H7, and H10 (¶0028).
Regarding claims 13-14, Nabel discloses a single nanoparticle with the first HA stem fused with an insect ferritin heavy chain and a second HA stem fused with an insect ferritin light chain (¶00107 and ¶00111-00112)
Regarding claim 16, Nabel discloses a linker which comprises SGG (Table 1 Description and SEQ ID NO: 43).
Regarding claims 17-18, Nabel discloses SEQ ID NO: 43 which comprises an amino acid sequence with 100% identity to instant SEQ ID NO: 1 (SEQ ID NO: 43).
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Regarding claims 21, 23, 27, and 29, Nabel discloses using the AS03 adjuvant (¶0208). AS03 consists of squalene, DL-α-tocopherol, and 4.86 mg of polysorbate 801 as evidenced by Yam, et al. (Front Immunol. 2015 Apr 29;6:207.) (pg. 2 column 1).
Regarding claim 31, Nabel discloses administering the HA stem polypeptide and adjutant vaccine to Cynomolgus Macaques to elicit an immune response that is 2-fold higher than the immune response to the vaccine without the adjuvant (¶0061 and Figure 25A-C).
Accordingly, Nabel anticipates the claimed inventions.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Nabel as applied to claims 1, 3-4, 6-14,16-18, 21, 23, 27, 29, and 31 above, and further in view of Impagliazzo, et al. (MY 182440 A, hereinafter “Impagliazzo”).
As discussed above claim 1 is anticipated by Nabel.
Regarding claim 5, Nabel teaches a synthetically stable stem polypeptide. Nabel does not teach that the stabilization is achieved by forming a homotrimer. However, Impagliazzo teaches that protein trimers increase stability of the protein. The native HA of influenza exists as a trimer on the cell surface, but most of the interactions between the monomers are located in the head domain. When the head is removed for HA stem immunogenic compositions, the protein destabilizes and modifications are required to reform the homotrimer which restabilizes the protein (pg. 37 lines 15-20).
It would have been prima facie obvious before the effective filing date of the claimed invention for one of ordinary skill in the art to have combined the teachings of Nabel of synthetically stabilized stem polypeptide and the teachings of Impagliazzo of an HA stem synthetically stabilized into a homotrimer. Impagliazzo provides motivation by teaching that the configuration of a homotrimer increases stability as compared to the monomer (pg. 37 lines 15-20). One of skill in the art would have had reasonable expectation of success at combining Nabel and Impagliazzo because they both teach HA stem influenza vaccines.
Accordingly, the claimed inventions were prima facie obvious to one of ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Nabel as applied to claims 1, 3-4, 6-14,16-18, 21, 23, 27, 29, and 31 above, and further in view of Rueckl, et al. (US 8778275 B2, hereinafter “Rueckl”) and Godeaux, et al. (Vaccine. 2015 Apr 27;33(18):2189-95., hereinafter “Godeaux”).
As discussed above claim 1 is anticipated by Nabel.
Regarding claim 31, Nabel teaches a kit containing the HA stem antigenic polypeptide particle and the squalene adjuvant in a single container (¶00195). Nabel does not teach keeping the antigen and adjuvant in two separate containers. However, Rueckl teaches a kit containing an influenza antigen in one container and the squalene adjuvant in a separate container. These containers can then be stored separately and mixed immediately before administration (¶129).
It would have been prima facie obvious before the effective filing date of the claimed invention for one of ordinary skill in the art to have combined the teachings of Nabel of a kit containing the HA stem antigenic polypeptide particle and the squalene adjuvant in a single container and the teachings of Rueckl of a kit containing an influenza antigen and squalene adjuvant in separate containers. Godeaux provides motivation by teaching that the shelf-life for antigens kept separately from adjuvants is longer than the shelf-life for pre-mixed antigens/adjuvants (Discussion ¶3). One of skill in the art would have had reasonable expectation of success at combining Nabel, Rueckl, and Godeaux because they all teach influenza vaccines.
Accordingly, the claimed inventions were prima facie obvious to one of ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Pieters, et al. (Chem. Soc. Rev. 2016, 45, 24-39
Pieters teaches proteins forming a homo-oligomeric assembly, like a homotrimer have many benefits including increasing stability (Introduction ¶1).
NO CLAIMS ARE ALLOWED
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Cassandra Senn Grizer whose telephone number is (571)272-2292. The examiner can normally be reached M-Th 0630 - 1700 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CASSANDRA SENN GRIZER/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
1 For claim 27, Examiner is interpreting consists essentially of following guidelines laid out in MPEP 2111.03. Adding D/L-α-tocopherol to the squalene emulsion adjuvant does not materially affect the basic and novel characteristics of the adjuvant as claimed.