DETAILED ACTION
Election/Restrictions
Applicant’s election of species NGFR and SEQ ID NO: 3, dated November 21, 2025, is acknowledged. Species NGFR was previously recited in claim 35, now canceled. No other claims recite this species. Claims 37-40 are withdrawn from consideration being directed to non-elected subject matter.
Claims Summary
Claims 32-34, 36 and 41-46
Claim 32 is directed to a method for preventing infection by a rabies virus in a mammal, comprising immunizing a mammal with an effective amount of a recombinant subunit vaccine comprising a soluble rabies viral surface antigen joined by in-frame fusion to a C-terminal portion of a collagen to form a disulfide bond-linked trimeric fusion protein. The rabies virus is a CTN-1 or a PM rabies virus (claim 33). The surface antigen comprises G protein or a fragment or epitope thereof (claim 34). The fusion protein comprises SEQ ID NO: 3 which is 750 amino acids in length, representing a CTN-1 G trimer without signal peptide. The trimer comprises 439 amino acids of the G protein (458 amino acids minus the 19-mer signal peptide), and 311 amino acids representing a trimer tag. The trimer tag comprises human C-propeptide of α1(I) collagen. The vaccine is administered via intramuscular injection (claim 41), intra-nasal spray (claim 42), in a single dose or a series of doses separated by intervals of weeks or months (claim 43), without adjuvant (claim 44), or with an adjuvant (claim 45), or with more than one adjuvant (claim 46).
Claims 47 and 48
Claim 47 is directed to a method for detecting antibodies to a rabies virus from sera of a mammal. The method comprises contacting the sera with a soluble rabies viral surface antigen, G protein or peptide (claim 48), joined by in-frame fusion to a C-terminal portion of collagen to form a disulfide bond-linked trimeric fusion protein.
Claims 49-51
Claim 49 is directed to a method of passive immunization comprising:
Immunizing a mammal with a soluble rabies viral surface antigen joined by in-frame fusion to a C-terminal portion of collagen to form a disulfide bond-linked trimeric fusion protein;
Purifying the neutralizing antibody generated; and
Treating patients infected by said rabies virus via passive immunization using the neutralizing antibody
The neutralizing antibody comprises polyclonal antibodies (claim 50), or is a monoclonal antibody (claim 51).
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.
Claim 51 is 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.
Claim 51 is directed to a method of passive immunization, comprising immunizing a mammal with a rabies trimeric fusion protein, purifying neutralizing antibodies generated by the mammal, and treating patients via passive immunization with the neutralizing antibodies, wherein the antibodies are monoclonal. The breadth of the claim reads on purifying a monoclonal antibody from a mammal. The nature of the invention is the production of neutralizing antibodies in mammals and then the use of those antibodies for passive immunization. Antibodies purified from mammals are polyclonal. The specification is not enabling for a method wherein monoclonal antibodies are purified from mammals since monoclonal antibodies are generated in laboratories and not isolated/purified from mammals (see page 2, first paragraph, of American Cancer Society, Monoclonal Antibodies and Their Side Effects, 6 pages, available from www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/monoclonal-antibodies.html, accessed January 6, 2026).
The specification does not provide any further guidance or working examples of purifying monoclonal antibodies from mammals. Therefore, in view of the breadth of the claim, the nature of the invention, the limited teachings of the specification, the lack of working examples, the state of the art, and the low level of predictability with regard to isolating monoclonal antibodies from a mammal, it would require undue experimentation to practice the method as claimed.
Claims 32-34, 41-46, 49 and 50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for some embodiments, does not reasonably provide enablement for all embodiments.
The breadth of claims 32-34 and 41-46 encompasses methods that employ a subunit vaccine for rabies, the subunit comprising a trimer of rabies virus surface antigen G protein, fragments or epitopes thereof. Embodiments that use the G protein or the ectodomain of the G protein are enabled as subunit unit vaccines having the claimed effect of preventing infection/disease. Embodiments that use fragments or epitopes of the G protein are not enabled as subunit unit vaccines having the claimed effect of preventing infection/disease.
The breadth of claims 49 and 50 encompasses passive immunization methods that obtain neutralizing antibodies from mammals immunized with a trimer of rabies virus surface antigen G protein, fragments or epitopes thereof, and administer them in a passive immunization method, thus preventing disease. Embodiments that use the G protein or the ectodomain of the G protein to immunize mammals are enabled as subunit unit vaccines having the claimed effect of generating neutralizing antibodies that are then used in a passive immunization method. Embodiments that use fragments or epitopes of the G protein are not enabled as subunit unit vaccines having the claimed effect of generating neutralizing antibodies that are then used in a passive immunization method. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The structure provided for the surface antigen is a fragment of no particular length of the G protein, or an epitope of the G protein. The specification provides one example of a fragment of the G protein, which is the ectodomain (G protein lacking the signal peptide amino acids 1-19) in Example 3. The specification provides numerous examples of epitopes, but none are made into trimers in the working examples. The Office does not doubt that trimers of fragments and epitopes can be produced, but whether they have the claimed function of preventing infection/disease or inducing antibodies that are able to induce passive immunity is the issue at hand.
Kaye et al. (Cureus, 2024, 16(6):e62429) provides a review of the state of the art in rabies vaccination. Rabies vaccines and candidates that use the G protein do not use fragments or epitopes only, rather, the intact G protein presented on virions, or G protein expressed from AAV (see Table 1). HRIG, which provides passive immunity, is produced from patients immunized with inactivated rabies virus vaccine which has intact G protein (see RxList, Imogam Rabies, 15 pages, available from www.rxlist.com/imogam-rabies-drug.htm, accessed January 7, 2026, last updated March 16, 2022).
In view of the breadth of the claims, the limited teachings of the specification and working examples regarding fragments and epitopes of the G protein, the state of the art, and the low level of predictability with regard to protection using fragments/epitopes of the G protein for achieving protection, it would require undue experimentation to practice the claimed methods. Amendment of the claims to require the surface antigen to comprise the G protein or its ectodomain would overcome this rejection.
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.
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.
Claims 32, 34 and 41-48 are rejected under 35 U.S.C. 103 as being unpatentable over Capecchi et al. (US 2008/0260769 A1, “Capecchi”) and Liang et al. (US 2005/0202537A1, “Liang”). The claims are summarized above and correlated with the teachings of the prior art in bold font below.
Capecchi discloses polypeptides for oligomeric assembly of antigens via fusion of an oligomeric polypeptide with an antigenic polypeptide (see abstract). Capecchi discloses rabies G protein as a trimeric surface protein, and suggests the formation of trimers using an oligomeric polypeptide (see paragraph [0051]) (claims 32, 34 and 48, aspect of rabies viral surface antigen G, subunit). Capecchi discloses the use of collagen oligomerization domains (see paragraph [0039]), and notes that the oligomerization domains using disulfide-linked monomers (see paragraph [0040]). However, Capecchi does not specifically disclose a C-terminal portion of a collagen that forms a disulfide bond-linked trimeric fusion protein. Given Capecchi’s suggestion to use any oligomerization domain, such as those from collagen, one would have been motivated to use Liang’s C-propeptide of collagen in the fusion protein in-frame with Capecchi’s rabies G polypeptide to form soluble trimers having disulfide bonds formed among three C-propeptides, with a reasonable expectation of success (see paragraph [0008]) (claim 32, aspects of in-frame fusion, C-terminal portion of a collagen, and soluble disulfide-bonded trimer).
Capecchi also discloses vaccines comprising the trimers for prophylactic immunization of mammals (see paragraphs [0108], [0110] and [0113]) (claim 32, aspect of immunization of mammals). Administration is intramuscular, intranasal or spray, and may be given in a single dose or multiple doses separated by weeks (see paragraphs [0115] and [0205]) (claims 41-43). Capecchi’s composition “usually” includes one or more adjuvants (see paragraph [0121]) (claims 45 and 46), which is also a disclosure of no adjuvant because of the term “usually” (claim 44). Capecchi discloses the detection of antibodies in sera from subjects immunized with the trimers (see paragraphs [0207] and [0208]) (claim 47). Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Capecchi et al. (US 2008/0260769 A1, “Capecchi”) and Liang et al. (US 2005/0202537A1, “Liang”) as applied to claim 32 above, and further in view of Wang et al. (Emerging Microbes & Infections, 2019, 8:1584-1592, “Wang”). Claim 33 is directed to an embodiment wherein rabies virus is a CTN-1 or PM strain.
The teachings of Capecchi and Liang are outlined above. While Capecchi discloses rabies virus generally, no particular strains are disclosed. It would have been obvious to have selected any known strain, such as CTN-1 or PM, motivated by their known use as vaccinal strains, with a reasonable expectation of success (see Wang, page 1584, left column, first paragraph). Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 49 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Capecchi et al. (US 2008/0260769 A1, “Capecchi”) and Liang et al. (US 2005/0202537A1, “Liang”), as applied to claim 32, and further in view of Manning et al. (MMWR, Recommendations and Reports, May 23, 2008, Vol. 57, No. RR-3, Human Rabies Prevention – United States, 2008, 36 pages, “Manning”).
The teachings of Capecchi and Liang are outlined above. Capecchi discloses immunization with the rabies trimers and observed neutralizing sera, but Capecchi does not suggest a method of purifying neutralizing antibodies from immunized subjects and administering them to patients in a method of passive immunization. However, it would have been obvious to have used the neutralizing sera for a method of passive immunization in view of Manning. Manning discloses the use of passive immunization for rabies using human rabies immune globulin (HRIG, obtained from human donors) comprising neutralizing antibodies (see page 1, Summary). One would have been motivated to use Capecchi’s neutralizing sera to obtain antibodies for a passive immunization method, just as Manning describes obtaining HRIG from human donors, with a reasonable expectation of success. Therefore, the claimed embodiments would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is allowed. Claim 36 is objected to for being dependent on a rejected claim but would otherwise be allowable if rewritten in independent form. Claim 36 is limited to SEQ ID NO: 3 which is free of the prior art of record.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Stacy B. Chen whose telephone number is 571-272-0896. The examiner can normally be reached on M-F (7:00-4:30). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone, can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/STACY B CHEN/Primary Examiner, Art Unit 1672