DETAILED ACTION
Applicant’s amendment and remarks filed April 8, 2026 are acknowledged. Claims 32, 33, 36, 41, 43, 44, 46-50 and new claims 52-58 are under examination. Claims 53, 55 and 58 recite various C-terminal polypeptides of collagen. Since Applicant has already elected SEQ ID NO: 3, which comprises the proα1(I) polypeptide, the election is also applied to claims 53, 55 and 58. Claims 37 and 40 remain withdrawn from consideration being directed non-elected subject matter.
Any prior objection or rejection that is not addressed or repeated below is either moot or withdrawn in view of Applicant’s amendment.
Claims Summary
Claims 32, 33, 36, 41, 43, 44, 46, 52 and 53
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 comprising a G protein or its ectodomain, joined by in-frame fusion to a C-terminal propeptide of a collagen to form a disulfide bond-linked trimeric fusion protein that is soluble. The rabies virus is a CTN-1 or a PM rabies virus (claim 33). 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 or intra-nasal spray (claim 41), or in a single dose or a series of doses separated by intervals of weeks or months (claim 43), or with or without adjuvant (claim 44), or with more than one adjuvant (claim 46). The C-terminal propeptide is of human collagen (claim 52). The C-terminal propeptide is the proα1(I) polypeptide (claim 53).
Claims 47, 48 and 54-56
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 propeptide of collagen to form a disulfide bond-linked trimeric fusion protein. The C-terminal propeptide is of human collagen (claim 54). The C-terminal propeptide is the proα1(I) polypeptide (claim 55). The fusion protein comprises SEQ ID NO: 3 (claim 56).
Claims 49, 50, 57 and 58
Claim 49 is directed to a method of passive immunization comprising:
Immunizing a mammal with a soluble rabies viral surface antigen G or its ectodomain, joined by in-frame fusion to a C-terminal propeptide of collagen to form a disulfide bond-linked trimeric fusion protein that is soluble;
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). The C-terminal propeptide is of human collagen (claim 57). The C-terminal propeptide is the proα1(I) polypeptide (claim 58).
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.
Claims 32, 41, 43, 44, 46-48 and 52-55 are rejected under 35 U.S.C. 103 as being unpatentable over Capecchi et al. (US 2008/0260769 A1, “Capecchi”) in view of 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 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]). Capecchi discloses polypeptides in oligomeric form that have been cleaved (see paragraph [0103]) (claim 1, aspect of soluble trimeric form). 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, such as proα1(I) of human 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 Liang, paragraphs [0008], [0011] and [0028]) (claims 32 and 52-55, aspects of in-frame fusion, C-terminal propeptide proα1(I) of a human 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 and 43). Capecchi’s composition “usually” includes one or more adjuvants (see paragraph [0121]) (claims 44 and 46), which is also a disclosure of no adjuvant because of the term “usually”. 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.
Applicant’s arguments filed April 8, 2026 have been carefully considered but fail to persuade. Applicant’s arguments are primarily directed to the following:
Applicant argues that Capecchi’s disclosure is directed to non-soluble constructs, noting that in the background section of the disclosure, Capecchi discusses the “soluble receptor” that removes transmembrane domains, in contrast to Capecchi’s constructs that include the transmembrane domains.
In response, while Capecchi discloses embodiments wherein cell membranes and host cells are administered (i.e., non-soluble polypeptides), Capecchi also discloses embodiments wherein polypeptides in oligomeric form are cleaved and used as immunogens (see paragraph [0103]). Therefore, Capecchi discloses immunogens that are not part of cell membranes and host cells, effectively, soluble.
Applicant argues that Capecchi does not teach or suggest in-frame fusion of the rabies antigens with a C-terminal propeptide of a collagen. Applicant notes that Capecchi’s exemplified embodiments comprise HIV gp120 and N. meningitidis adhesin NadA, which are different from the instantly claimed embodiment of rabies G and C-terminal propeptide of a collagen.
In response, the rejection acknowledges that Capecchi does not teach a C-terminal propeptide of a collagen, which is why the rejection also relies on the Liang reference. As for the differences between HIV gp120 and rabies G, and NadA and a C-terminal propeptide of a collagen, Applicant has not provided any evidence as to how the differences would preclude doing what the prior art suggests.
Applicant argues that Liang does not disclose an in-frame fusion of the propeptide with a viral antigen, such as rabies G, nor that such fusion proteins can induce and bind specific antibodies. Applicant notes that those of skill in the art would recognize that an in-frame fusion of two polypeptides may impact the spatial structures such that immunogenicity is altered. Applicant argues that one would not have known whether the in-frame fusion would have resulted in a fusion protein that induces neutralizing antibodies, as was shown in Applicant’s own work in examples 3 and 4 of the specification.
In response, the rejection acknowledges that Liang does not disclose an in-frame fusion with rabies G specifically, rather, Liang discloses an in-frame fusion with any soluble receptor or biologically active polypeptide (see paragraph [0008]). Although Applicant essentially asserts that one would not have expected Liang’s generic disclosure to apply to rabies G absent experimentation demonstrating such, Applicant has not presented any evidence to the contrary other than an assertion that spatial alterations due to the in-frame fusion would disrupt immunogenicity. However, Applicant’s work actually shows that immunogenic fusion proteins result from doing what the prior art suggests (as set forth in the rejection above). Therefore, the rejection is maintained for reasons of record.
Claim 33 remains 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. Applicant’s arguments have been addressed above.
Claims 49, 50, 57 and 58 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 claims 32 and 52-55 above, 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. Applicant’s arguments have been addressed above.
Conclusion
No claim is allowed. Claims 36 and 56 are objected to for being dependent on rejected claim but would otherwise be allowable if rewritten in independent form. Claims 36 and 56 are limited to SEQ ID NO: 3 which is free of the prior art of record.
Applicant's amendment necessitated the new ground(s) 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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
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.
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
Prosecution Insights