DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 21, 2026 has been entered.
Claims Summary
In the amendment of September 21, 2026, claim 32 has been amended to recite C-terminal propeptides selected from SEQ ID NO: 16-31. In the election of species requirement of October 3, 2025, Applicant was required to elect one fusion protein sequence from SEQ ID NO: 3, 4, 5, 6 and 10. If SEQ ID NO: 10 was elected, then Applicant was to further elect one of SEQ ID NO: 16-31. Since Applicant did not elect SEQ ID NO: 10, the election from SEQ ID NO: 16-31 did not apply. Claim 32 now recites SEQ ID NO: 16-31. Although SEQ ID NO: 10 was not elected, upon further consideration, it is now rejoined with the elected species, SEQ ID NO: 3, since SEQ ID NO: 10 is part of SEQ ID NO: 3. Similarly, SEQ ID NO: 4 is also rejoined because it has SEQ ID NO: 3 in its sequence. As for an election from SEQ ID NO: 16-31, the examiner has looked to SEQ ID NO: 3 and 4 for their respective collagen propeptide sequences, which are SEQ ID NO: 16 and 18. Thus, SEQ ID NO: 16 and 18 are effectively elected and the others are withdrawn from consideration.
In summary, claims 32, 33, 36, 37, 40, 41, 43, 44, 46-50 and 56 are under examination with regard to the elected species of SEQ ID NO: 3, 4, 10, 16 and 18, as applicable.
Claims 32, 33, 36, 37, 40, 41, 43, 44 and 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 comprising a G protein ectodomain, joined by in-frame fusion to a N-terminus of a C-terminal propeptide of a collagen to form a disulfide bond-linked trimeric fusion protein that is soluble, wherein the propeptide comprising SEQ ID NO: 16 or SEQ ID NO: 18 (claims 32 and 40). The rabies virus is a CTN-1 or a PM rabies virus (claim 33).
The fusion protein comprises SEQ ID NO: 10, representing a CTN-1 G protein, lined to SEQ ID NO: 16 or 18 (claim 40).
The fusion protein comprises SEQ ID NO: 3 which is 750 amino acids in length, representing a CTN-1 G trimer without signal peptide (claim 36). 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. SEQ ID NO: 3 comprises a C-terminal propeptide comprising SEQ ID NO: 16 (244-aa).
The fusion protein comprising SEQ ID NO: 4 which is 769 amino acids in length, similar to SEQ ID NO: 3, except that SEQ ID NO: 4 comprises a C-terminal propeptide comprising SEQ ID NO: 18 (309-aa) (claim 37).
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).
Claims 47, 48 and 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, wherein the C-terminal propeptide is selected from SEQ ID NO: 16 and 18. The fusion protein comprises SEQ ID NO: 3 (claim 56).
Claims 49 and 50
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; the C-terminal propeptide is selected from SEQ ID NO: 16 and 18.
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).
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.
(New Rejection) Claims 32, 33, 36, 37, 40, 41, 43, 44 and 46 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 a method for inhibiting infection by a rabies virus in a mammal, does not reasonably provide enablement for preventing an infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 32 and its dependent claims are directed to a method of preventing an infection, which is understood to encompass the embodiment of no infection at all (i.e., not one virion infects one cell). Paragraph [0232] of this application’s published application (US 20230218739) notes that prevention includes prophylaxis with respect to the occurrence or recurrence of a disease. However, that definition of prevention is open to other meanings, such as zero infected cells. Since this level of prevention is not possible, the enabled embodiment is “inhibition” of an infection that prevents rabies virus disease, which is in line with the nature of the invention, i.e., an infection occurs followed by an immune response that will prevent the infection from causing disease.
In view of the breadth of the claims, the nature of the invention, the lack of working examples and teachings in the specification demonstrating the level of prevention outlined above, and the lack of predictability to completely prevent an infection, it would require undue experimentation to practice the claimed invention. Suggested language to overcome this rejection is “A method for inhibiting a rabies virus infection in a mammal”, or equivalent language.
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.
(New Rejection) Claims 32, 41, 43, 44 and 46-48 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”) and Bandyopadhyay et al. (WO 2012/049560 A1, “Bandyopadhyay”). Previously, this rejection did not include the Bandyopadhyay reference. It is added here to address the new limitation in claim 32 regarding the sequences of the propeptide. 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), wherein the order of components is an antigenic domain, an oligomerization domain, and a transmembrane domain, running from C- to N-, or N- to C- terminus (see paragraph [0010]) (claim 32, aspect of N-terminus). 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).
Capecchi does not specifically disclose a C-terminal portion of a collagen that forms a disulfide bond-linked trimeric fusion protein. Capecchi’s example of a collagen oligomerization domain is from the NC1 domain of type X collagen (see paragraph [0039]). However, Capecchi’s teachings concerning collagen oligomerization domain are not limited to that example. Given Capecchi’s suggestion to use a collagen oligomerization domain, and the teaching that oligomers containing disulfide-linked monomers can be used, 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]) (claim 32, 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).
Liang does not appear to disclose Applicant’s SEQ ID NO: 16 as the sequence for proα1(I) of human collagen. However, it would have been obvious to have used any known sequence of proα1(I) of human collagen with a reasonable expectation of success, such as the sequence disclosed in Bandyopahyay as SEQ ID NO: 1, which is 246-aa and is identical in content with Applicant’s SEQ ID NO: 16 (244-aa). Bandyopahyay’s SEQ ID NO: 1, amino acids 3-246 are identical to amino acids 1-244 of Applicant’s SEQ ID NO: 16 (claim 32, aspect of SEQ ID NO: 16). 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 September 21, 2026 have been carefully considered but fail to persuade. Applicant’s arguments are primarily directed to the following:
Applicant argues that the C-terminal polypeptides of SEQ ID NO: 16-31, recited in claim 32, belong to type I and type III collagens. These differ in structure from the type X collagen disclosed in Capecchi, differing in length, function and sequence homology. Applicant argues that Capecchi does not teach or fairly suggest using any oligomerization domain, rather, Capecchi is limited to the ones specifically mentioned. Applicant argues that one would not have known, without experimentation, whether Capecchi’s rabies virus G protein in combination with a collagen I or III C-terminal propeptide would result in a disulfide bond-linked trimeric fusion protein that is immunogenic.
In response, as outlined above, the Office acknowledges that Capecchi does not specifically disclose a C-terminal portion of a collagen that forms a disulfide bond-linked trimeric fusion protein. Capecchi’s example of a collagen oligomerization domain is from the NC1 domain of type X collagen (see paragraph [0039]). However, Capecchi’s teachings concerning collagen oligomerization domain are not limited to that example. Given Capecchi’s suggestion to use a collagen oligomerization domain, and the teaching that oligomers containing disulfide-linked monomers can be used, 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]). Liang discloses that “any soluble receptors or biologically active polypeptides to be made into trimeric forms as secreted proteins”, referring to fusions in-frame with the C-propeptide domain of fibrillar collagen for trimerization (see paragraph [0008]). Liang’s teachings are Applicant’s own work. Given Liang’s teachings, one would have had motivation and a reasonable expectation of success to use proα1(I) of human collagen in Capecchi’s oligomerization construct.
Applicant argues that the immunogenicity of a viral antigen and its ability to be bound by neutralizing antibodies depends on epitope conformation and location, thus one would not have been able to foresee whether a viral surface antigen fused to a trimerization domain would result in an antigenic epitope that is bound by neutralizing antibodies. Applicant notes that Capecchi’s exemplified embodiments comprising HIV gp120 and gp140 fused to the same trimerization domain, N. meningitidis adhesin NadA, resulted in inducing neutralizing antibodies and no neutralizing antibodies, respectively. Applicant argues that these results show that a trimerization domain has an impact on the epitope conformation of the fused antigen.
In response, the Office acknowledges the general principle that epitope presentation impacts immunogenicity. However, in this case, Capecchi discloses immunogenic trimers formed by oligomerization domains, of which Liang discloses oligomerization domains that form trimers and are immunogenic. Thus, one would have had a reasonable expectation of success that a fusion of rabies virus G with Liang’s propeptide would result in a timer that is immunogenic. The structure of the subunit vaccine recited in the claims is the same structure that is suggested by the prior art. There are no further structural limitations concerning the spacing of the G protein and the propeptide recited in Applicant’s claims. If such features detailing the spacing of the antigen from the trimerization domain are critical to the function of subunit vaccine in the claims, then such limitations should be added to the claims. Lacking any further evidence to the contrary, the rejection is maintained for reasons of record.
(New Rejection) Claim 33 is 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”) and Bandyopadhyay et al. (WO 2012/049560 A1, “Bandyopadhyay”) 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, Liang and Bandyopadhyay 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.
(New Rejection) Claim 40 is 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”) and Bandyopadhyay et al. (WO 2012/049560 A1, “Bandyopadhyay”) as applied to claim 32 above, and further in view of Sun et al. (CN 109111507A, published January 1, 2019, English translation provided by Clarivate, 2026, 16 pages). Claim 40 is directed to an embodiment wherein the fusion protein comprises SEQ ID NO: 10 fused at its C-terminus, either directly or indirectly with the N-terminus of SEQ ID NO: 16.
The teachings of Capecchi, Liang and Bandyopadhyay are outlined above. Capecchi does not appear to disclose SEQ ID NO: 10 as a rabies virus G sequence. However, it would have been obvious to have selected any known G sequence for the fusion protein, such as the G sequence disclosed by Sun, with a reasonable expectation of success. Sun’s SEQ ID NO: 1, amino acids 21-259 is an exact match with amino acids 1-439 of Applicant’s SEQ ID NO: 10. 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.
(New Rejection) Claims 49 and 50 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”) and Bandyopadhyay et al. (WO 2012/049560 A1, “Bandyopadhyay”), as applied to claim 32 above as it pertains to the recombinant subunit vaccine, 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, Liang and Bandyopadhyay 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.
Claim 56 is objected to for being dependent on a rejected claim but would otherwise be allowable if rewritten in independent form.
SEQ ID NO: 3 and 4 are free of the prior art of record.
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/STACY B CHEN/Primary Examiner, Art Unit 1672
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