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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/3/25 has been entered.
Claims 1, 7, 18, 23, 25-27, 29-31, 35, 36, and 38-48 are pending and currently under consideration.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 1, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Dimitrov et al (WO 2009/137632 A2; 11/12/09; 3/14/19 IDS) in view of Haynes et al (US 2006/0014148 A1; 1/19/06), Berman et al (Nature, 1990, 345: 622-625), Wibmer et al (PLOS Pathogens, 2017, e1006074; 1-30), and Kovacs et al (PNAS, 2014, 111(52): 18542-18547; 5/27/21 IDS).
The claims of this application are drawn to immunogenic fusion proteins comprising components known to generate an immunogenic response to HIV (gp41 and gp120) linked to a component taught to enhance immunogenicity of the fusion proteins and routinely used in the art to extend half-life of fusion proteins (Fc domain), methods using such immunogenic fusion proteins, reagents used to make such immunogenic fusion proteins, and methods of making such immunogenic fusion proteins.
Dimitrov et al teaches highly stable and immunogenic fusion proteins comprising (i) an immunogenic portion of HIV envelope (env domain) protein gp41 and (ii) an Fc domain of an antibody that elicit broadly cross-reactive HIV neutralizing antibodies and can be used in method of treating a subject with HIV and/or vaccinating a subject against an HIV infection by administering the fusion proteins (Abstract, in particular). Dimitrov et al further teaches said immunogenic fusion proteins wherein the immunogenic portion of HIV envelope (env domain) is fused to the Fc domain via a flexible linker having 1-50 amino acids in length (such as a hinge domain) and that the linker can be “any linker envisioned by one of skill in the art” or the immunogenic portion of HIV envelope (env domain) can be fused directly to an Fc domain in the absence of a linker (lines 16-19 on page 5, lines 27-30 on page 7, and lines 3-6 on page 33 in particular). Dimitrov et al further teaches the Fc domain IgG is the CH2-CH3 region of an antibody (see legend of Figure 10 “…the CH2-CH3 (Fc region) of human IgG…”, in particular). Dimitrov et al further teaches the Fc domain can be an Fc domain of any IgG, IgA, IgM, or IgE antibody (lines 14-15 on page 5, in particular). One of skill in the art would further recognize Fc domains of IgM and IgE antibodies lack hinge domains/regions. Dimitrov et al further teaches SEQ ID NO: 5 as an IgG Fc domain lacking a hinge domain that is an “Fc receptor ligand” (see “In yet another embodiment…the Fc receptor ligand component of the immunogen of the invention is the CH2-CH3 region of a human IgG having the amino acid sequence of SEQID NO:5” at lines 1-3 on page 6, in particular), which is a monomeric Fc domain that lacks the hinge domain of SEQ ID NO:6 (compare sequences of Figures 10-11, in particular). Lines 12-16 on page 20 of Dimitrov et al teach an “Fc receptor ligand” “…refers to any Fc region (or fragment thereof) capable of being specifically recognized and/or bound by an Fc receptor and which causes the Fc receptor to become activated, thereby triggering the downstream physiological responses associated with binding of an Fc receptor with an Fc region.” Dimitrov et al further teaches the Fc domain of the fusion proteins enhance immunogenicity of the fusion proteins by enabling the fusion proteins to bind immune cells with Fc receptors and contribute to a potentially longer half-life of the fusion proteins (lines 8-14 on page 14 and lines 2-5 on page 71, in particular). Dimitrov et al further teaches gp41 comprises an extracellular domain (ectodomain), a transmembrane domain, and a cytoplasmic domain (lines 27-28 on page 2, in particular). Dimitrov et al further teaches said fusion proteins wherein the immunogenic portion of HIV gp41 of the fusion proteins lacks the oligomeric transmembrane region of gp41 (lines 4-7 on page 5, in particular). Dimitrov et al further teaches gp41Fc as an example of an immunogenic fusion protein lacking a transmembrane domain and comprising (i) HIV gp41 joined via a long flexible linker hinge domain (regions “ed” and “2” of Figure 1, in particular) to (ii) a region that is not encoded by HIV consisting of an Fc domain (region “3” Figure 1, in particular). Dimitrov et al further teaches gp41Fc comprises a CD5ss signal/leader peptide (Figures 1 and 13, in particular). Dimitrov et al further teaches because gp41Fc is cross-reactive with at least five different HIV-1-neutralizing antibodies, gp41Fc could potentially elicit such HIV-1-neutralizing antibodies (lines 4-14 on page 60, in particular). Dimitrov et al further teaches gp41Fc bound to a solid support, such as a microtiter plate, for assaying a composition comprising an HIV antibody (page 65, in particular). Dimitrov et al further teaches methods of producing an antibody comprising administering gp41Fc to an animal (lines 8-10 on page 6 and lines 14-16 on page 9, in particular). Dimitrov et al further teaches a nucleic acid vector comprising a promoter operatively linked to a nucleic acid sequence encoding gp41Fc for transient transection into mammalian free-style 293 cells (a type of “HEK293” cells) for preparing gp41Fc fusion proteins that are purified from cell culture supernatant (page 64, in particular). Dimitrov et al further teaches a method comprising contacting a sample containing an antibody and gp41Fc and determining the binding affinity between the antibody and gp41Fc (lines 2-6 on page 65, in particular). Dimitrov et al further teaches the ability of an antibody to bind a particular antigen can be described as an affinity and that such an affinity can be measured by ELISA or other suitable affinity tests (page 17, in particular). Dimitrov et al further teaches screening antibody libraries for antibodies that specifically bind gp41 of gp41Fc (claim 36, in particular). Dimitrov et al further teaches gp41 fusion proteins can be used diagnostically to detect anti-HIV antibodies in a sample (lines 15-16 on page 32, in particular). Dimitrov et al further teaches gp41 and gp120 are generated by proteolytically processing the gp160 precursor Env protein (lines 8-13 on page 2, in particular). Dimitrov et al further teaches both gp41 and gp120 are known to generate an immune response during HIV infection (lines 11-12 on page 3, in particular) and that neutralizing antibodies have been generated against gp120 (lines 4-8 on page 3, in particular).
Dimitrov et al does not specifically describe immunogenic fusion proteins of Dimitrov et al as including “at least four epitopes of the HIV envelope protein” or describe fusion proteins comprising both gp120 and gp41 epitopes that are connected by amino acid sequences not encoded by HIV. However, these deficiencies are made up in the teachings of Haynes et al, Berman et al, Wibmer et al, and Kovacs et al.
Haynes et al teaches methods of inducing anti-HIV antibodies using a fusion protein comprising an HIV envelope component and an Fc domain ([0007], [0011], and claim 18, in particular). Haynes et al further teaches such an Fc domain provides fusion proteins with a longer serum/plasma/extracellular fluid half-life ([0012], in particular). Haynes et al further teaches generating such Fc fusion proteins with HIV envelope components as gp41, gp120, gp140, or gp160 ([0012] and claim 9, in particular). Haynes et al further demonstrates generating fusion proteins comprising pg120 and an Fc domain (see “IgFc/gp120/C3d” of [0019] and claim 9, in particular). The components gp41 and gp120 are generated by proteolytically processing the gp160 precursor Env protein (as evidenced by lines 8-13 on page 2 of Dimitrov et al) and gp140 contains both gp120 and gp41 (as evidenced by Example 1 of Dimitrov et al, in particular).
Berman et al teaches vaccination with recombinant gp120 protects chimpanzee subjects from HIV infection (Abstract, in particular). Berman et al further teaches generating gp120 and gp160 constructs comprising expressing vectors encoding said constructs in CHO cells (Figure 1, in particular).
Wibmer et al teaches epitopes of numerous HIV neutralizing antibodies found on gp41 and gp120 (page 18 and Figure 8, in particular).
At the left column on page 18542, Kovacs et al teaches how the major HIV viral surface antigen (envelope spikes) is formed. First, the gp160 precursor Env protein of HIV trimerizes and then undergoes cleavage by a furin-like protease into gp41 and gp120. Subsequently, three copies of each of gp120 and gp41 form the envelope spike (gp120/gp41)3, the major surface antigen of HIV. Kovacs et al further teaches a vaccine strategy that uses a recombinant polypeptide comprising gp120 linked via a non-HIV 20-amino acid linker sequence (SGGGG)4 to gp41, which can oligomerize into an uncleaved ectodomain of trimeric (gp120/gp41)3 (see “Significance” box on page 18542, in particular). Kovacs et al further teaches that as compared to (gp120/gp41)3 structures lacking the 20-amino acid linker, constructs comprising the 20-amino acid linkers not encoded by HIV form a compact, native-like (gp120/gp41)3 oligomeric structure with many antigenic properties expected from a functional envelope spike and that these recombinant polypeptides comprising the 20-amino acid linker are “promising envelope immunogens for inducing neutralizing antibody responses.” See “Significance” box on page 18542 and Figure 1, in particular.
One of ordinary skill in the art would have been motivated, with an expectation of success, to perform a combined method comprising generating (using cells of Dimitrov et al or Berman et al comprising nucleic acid nucleic acids encoding immunogenic fusion proteins operably linked to a promoter) and administering to just any animal (including human) subjects having, or at risk for HIV infection, immunogenic fusion proteins comprising monomeric Fc of Dimitrov et al without a hinge domain fused directly to, or fused via a flexible linker having 1-50 amino acids in length that can be “any linker envisioned by one of skill in the art” (such a 20-amino acid linker not encoded by HIV (SGGGG)4 of Kovacs et al), “gp140-FL20” of Fig 1 of Kovacs et al comprising (N-terminus-to-C-terminus) gp120 linked via a non-HIV sequence 20-amino acid linker (SGGGG)4 to gp41 because Dimitrov et al teaches immunogenic fusion proteins comprising monomeric Fc without a hinge domain linked directly to, or fused using a flexible linker having 1-50 amino acids in length that can be “any linker envisioned by one of skill in the art”, gp41 are used to elicit anti-envelope protein HIV neutralizing antibodies and can be used in methods of treating a subject with HIV and vaccinating a subject against an HIV infection by administering such fusion proteins and, like gp41 of the immunogenic fusion proteins comprising Fc of Dimitrov et al, gp120 of “gp140-FL20” of Kovacs et al is taught by cited references to also elicit anti-envelope protein HIV neutralizing antibodies for vaccinating a subject against HIV infection. Further, Kovacs et al teaches recombinant polypeptides comprising gp120 linked via a non-HIV sequence 20-amino acid linker (SGGGG)4 to gp41 (“gp140-FL20”) oligomerize to form compact, native-like (gp120/gp41)3 oligomeric structure with many antigenic properties expected from a functional envelope spike and that these recombinant polypeptides comprising the 20-amino acid linker are “promising envelope immunogens for inducing neutralizing antibody responses.” See “Significance” box on page 18542, in particular. Further, Dimitrov et al teaches SEQ ID NO: 5 as an Fc domain that is an “Fc receptor ligand” (see lines 1-3 on page 6and lines 11-12 on page 12, in particular) which lacks the hinge domain of SEQ ID NO:6 (compare sequences of Figures 10-11, in particular), Dimitrov et al teaches said Fc domain enhances immunogenicity of the fusion proteins by enabling the fusion proteins to bind immune cells with Fc receptors and contribute to a potentially longer half-life of the fusion proteins (lines 8-14 on page 14 and lines 2-5 on page 71, in particular), and [0012] of Haynes et al also recognizes inclusion such Fc domains provides fusion proteins with a longer serum/plasma/extracellular fluid half-life. Fusion proteins of the combined method, wherein env domain is fused directly to (or fused via the linker of Kovacs et al) the Fc domain of SEQ ID NO:5 comprise monomeric Fc domains lacking the hinge domain of SEQ ID NO:6. Further, one would be motivated, with an expectation of success, to generate said fusion proteins without a transmembrane domain in order to generate anti-envelope protein HIV neutralizing antibodies against exposed (as opposed to not exposed transmembrane domains) domains.
Immunogenic fusion proteins of the combined method include:
[gp140-FL20 of Kovacs]-[(SGGGG)4 flexible linker of Kovacs]-[hingeless Fc domain of Dimitrov]
[gp140-FL20 of Kovacs]-[hingeless Fc domain of Dimitrov]
Regarding claim 48, the “hingeless Fc domain of Dimitrov” of each above fusion protein has HIV gp120 (and epitopes thereof) located at the N-terminal side of “gp140-FL20” of Kovacs and HIV gp41 (and epitopes thereof) at the C-terminal side of “gp140-FL20” of Kovacs (see Figure 1 of Kovacs et al for structure of “gp140-FL20”).
Further, one of ordinary skill in the art would have been motivated, with an expectation of success, to perform the combined method of generating the immunogenic fusion proteins wherein an N-terminal CD5ss signal/leader peptide of Dimitrov et al is present on the fusion proteins (just as Figure 2 of Haynes et al illustrates the “CD5 secrational signal” is present on fusion proteins of Haynes et al) because one of skill in the art would recognize such a signal/leader peptide would predictably promote secretion of the fusion protein during the process of generating the fusion protein (as exemplified by Example 1 of Dimitrov et al with gp41Fc).
Further, one of ordinary skill in the art would have been motivated, with an expectation of success, to diagnose subjects as having or not having HIV by determining whether anti-HIV antibodies that bind fusion proteins of the combined method attached to a solid support of Dimitrov et al are present in samples and select/characterize those sample not having anti-HIV antibodies that bind the fusion proteins of the combined method as being derived from subjects not having HIV because Dimitrov et al teaches envelope proteins can be used diagnostically to detect anti-HIV antibodies in a sample (lines 15-16 on page 32, in particular) and Dimitrov et al teaches HIV-specific antibodies can be detected by contacting a sample with envelope protein-Fc fusion proteins attached to a solid support and determining the binding between the antibody and fusion proteins (lines 2-6 on page 65, in particular).
Immunogenic fusion proteins of the combined method predictably include those with at least one gp120 epitope, at least one gp41 epitope, and at least five total epitopes of the HIV envelope protein due to: (i) gp41 comprising a portion of the HIV envelope protein and is taught by Dimitrov et al to cross-react with at least five different HIV-1-neutralizing antibodies (lines 4-14 on page 60, in particular), (ii) epitopes of numerous known HIV neutralizing antibodies found on the HIV envelope proteins gp41 and gp120 (page 18 and Figure 8 of Wibmer et al, in particular), and (iii) the claims are not drawn to constructs comprising epitopes of particular anti-gp41 or anti-gp120 antibodies and include epitopes of just any imaginable anti-gp41 or anti-gp120 antibodies. One of skill in the art would recognize distinct epitopes of gp41 and gp120 are responsible for eliciting distinct antibodies.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 12/3/25, Applicant argues cited references do not teach or suggest “a region that is not encoded by HIV, said region consisting of a monomeric Fc domain of an antibody that lacks a hinge region” of claim 1 or contemplate omission of a hinge region. Applicant further provides a Declaration by Melton Witt, which argues one of ordinary skill would not have understood Dimitrov to suggest a monomeric Fc domain of an antibody that lacks a hinge region and Dimitrov discloses, teaches, and suggests an Fc region with a hinge region intended to activate Fc receptor. Applicant further argues one of ordinary skill in the art would not have been motivated to omit a hinge region and would have had no reasonable expectation of success in doing so because it would have been counterintuitive based on knowledge extant in the art, Dimitrov did not disclose a fusion protein with an incomplete Fc receptor ligand or provide any disclosure, teaching, or suggestion that doing so would result in a functional construct, and it is clear from Dimitrov that a construct of Dimitrov is solely intended to activate Fc receptor and in order to do so Fc receptor ligand of the construct must be complete with a hinge region to dimerize. The declaration indicates one of ordinary skill in the art would have expected the hinge region of an Fc domain to be required to generate an immune response by binding and activating an Fc receptor and an Fc domain lacking a hinge region would not be able to dimerize to function as an Fc receptor ligand. Applicant further cites Table 1, Example 4, and Env40, Env41, Env43, Env44, Env46, and Env48 constructs disclosed by the instant specification and argues the claimed fusion proteins are non-obvious because constructs encompassed by the claims unexpectantly and surprisingly provided unique hits of HIV antibodies even when the Fc domain lacks a hinge region.
The amendments to the claims, the Declaration by Melton Witt, and the arguments found in the Reply of 12/3/25 have been carefully considered, but are not deemed persuasive. In regards to the arguments that cited references do not teach or suggest “a region that is not encoded by HIV, said region consisting of a monomeric Fc domain of an antibody that lacks a hinge region” of claim 1, cited references do not contemplate omission of a hinge region, the argument in the carefully-considered Declaration by Melton Witt that one of ordinary skill would not have understood Dimitrov to suggest a monomeric Fc domain of an antibody that lacks a hinge region and Dimitrov discloses, teaches, and suggests an Fc region with a hinge region intended to activate Fc receptor, one of ordinary skill in the art would not have been motivated to omit a hinge region and would have had no reasonable expectation of success in doing so because it would have been counterintuitive based on knowledge extant in the art, Dimitrov did not disclose a fusion protein with an incomplete Fc receptor ligand or provide any disclosure, teaching, or suggestion that doing so would result in a functional construct, and it is clear from Dimitrov that a construct of Dimitrov is solely intended to activate Fc receptor and in order to do so Fc receptor ligand of the construct must be complete with a hinge region to dimerize, and the indication one of ordinary skill in the art would have expected the hinge region of an Fc domain to be required to generate an immune response by binding and activating an Fc receptor and an Fc domain lacking a hinge region would not be able to dimerize to function as an Fc receptor ligand: It is first noted the, while Dimitrov et al discloses embodiments of binding and/or activating Fc receptor, the instant claims do not recite binding and/or activation of Fc receptor. Further, the examiner maintains Dimitrov et al suggests constructs that do not have a hinge domain (as well as constructs that do have a hinge domain). Dimitrov et al suggests constructs using Fc domains from IgE and IgM antibodies (lines 14-15 on page 5, in particular), which comprise beta sheet domains and do not comprise hinge domains (as evidenced by Figure 1(b) and right column on page 62 of Brezski et al (Current Opinion in Immunology, 2016, 40: 62-69)). Dimitrov et al further suggests constructs comprising an Fc domain wherein the env domain is fused via a flexible linker having 1-50 amino acids in length (such as a hinge domain) and that the linker can be “any linker envisioned by one of skill in the art” or the immunogenic portion of HIV envelope (env domain) can be fused directly to an Fc domain in the absence of a linker (lines 16-19 on page 5, lines 27-30 on page 7, and lines 3-6 on page 33 in particular). Dimitrov et al further suggests constructs using SEQ ID NO: 5 as an IgG Fc domain that is an “Fc receptor ligand” (see “In yet another embodiment…the Fc receptor ligand component of the immunogen of the invention is the CH2-CH3 region of a human IgG having the amino acid sequence of SEQID NO:5” at lines 1-3 on page 6, in particular), which is a monomeric Fc domain that lacks the hinge domain of SEQ ID NO:6 (compare sequences of Figures 10-11, in particular). In regards to activation of Fc receptor, Dimitrov et al teaches Fc receptors are activated by binding Fc regions or fragments thereof (lines 12-16 of Dimitrov et al, in particular). Dimitrov et al does not teach monomeric Fc constructs and/or Fc constructs lacking a hinge domain would not bind or activate Fc receptors. Rather, Dimitrov et al teaches generating constructs using SEQ ID NO:5, which is described at lines 1-3 on page 6 by Dimitrov et al as an “Fc receptor ligand” (is bound by Fc receptor) that is a monomeric domain that lacks a hinge domain (compare sequences of Figures 10-11). Further, lines 12-16 on page 20 of Dimitrov et al teach an “Fc receptor ligand” “…refers to any Fc region (or fragment thereof) capable of being specifically recognized and/or bound by an Fc receptor and which causes the Fc receptor to become activated, thereby triggering the downstream physiological responses associated with binding of an Fc receptor with an Fc region.” By Dimitrov et al teaching an Fc domain that lacks a hinge domain as an “Fc receptor ligand”, Dimitrov et al provides no indication that an Fc domain that lacks a hinge domain is to be disparaged as an “incomplete ligand agonist” of an Fc receptor. Rather, based on the definition of “Fc receptor ligand” of Dimitrov et al, it appears Dimitrov et al would consider the hingeless Fc domain of SEQ ID NO:5 to be a complete ligand agonist of an Fc receptor. Further, teachings of cited references are not limited to working examples. Further, lines 9-14 on page 14 of Dimitrov et al discuss immunogenic constructs with, or without (see “optionally), a flexible linker (such as a hinge):
“…gp41-based antigens provided by the invention fuse HIV gp41 or a fragment thereof (e.g., gp41 ectodomain) with an Fc receptor ligand, e.g., the Fc region of human IgG), optionally through a flexible linker (e.g., the hinge region of human IgG), wherein the gp41 fusion protein stabilizes the structure of gp41 in the absence of gp120, and exhibits enhanced immunogenicity by enabling it to bind to immune cells having Fc receptors, such as, macrophages or dendritic cells.”
Further, the prior art indicates that monomeric constructs comprising an Fc region and lacking a dimerizing hinge domain predictably bind Fc receptors (and are “Fc receptor ligands”). For instance, Radaev et al (Molecular Immunology, 2001, 1073-1083) teaches monomeric antibodies (where Fc receptors are not dimerized) are known in the prior art to activate high affinity Fc receptors FceRI and FCgRI (right column on page 1073 of Radaev et al). FceRI is an Fc receptor that binds the Fc portion of IgE (which lacks a hinge domain). FCgRI is an Fc receptor that binds the Fc portion of IgG.
In regards to the citation of Table 1, Example 4, and Env40, Env41, Env43, Env44, Env46, and Env48 constructs disclosed by the instant specification and argument the claimed fusion proteins are non-obvious because constructs encompassed by the claims unexpectantly and surprisingly provided unique hits of HIV antibodies even when the Fc domain lacks a hinge region, the ability to obtain unique “hits” of HIV antibodies from different constructs lacking hinge regions is predictable because the constructs differ in structure. In regards to a given disclosed structure to “unexpectedly” interact with a given HIV antibody, it is noted objective evidence of non-obviousness must be commensurate in scope with the claimed for which evidence is offered to support. MPEP 716.02(d). The claims are not limited to any particular “Env” fusion protein illustrated in the specification that interacts with any particular combination of HIV antibodies. Further, one of skill in the art would recognize hinge regions are not required for fusion proteins to bind antibodies.
Claim Rejections – 35 USC § 103
Claim(s) 1, 18, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 remain rejected under U.S.C. 103 as being unpatentable over Dimitrov et al (WO 2009/137632 A2; 11/12/09; 3/14/19 IDS) in view of Haynes et al (US 2006/0014148 A1; 1/19/06), Berman et al (Nature, 1990, 345: 622-625), Wibmer et al (PLOS Pathogens, 2017, e1006074; 1-30), and Kovacs et al (PNAS, 2014, 111(52): 18542-18547; 5/27/21 IDS), as applied to claims 1, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 above, and further in view of Terpe (Appl Microbiol Biotechnol, 2003, 60: 523-533).
Teachings of Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al are discussed above. Dimitrov et al further envisions “any suitable method” for purifying antigens (e.g., gp41Fc) of Dimitrov et al (page 47, in particular).
Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al do not specifically teach the fusion proteins of the combined method including a His-tag. However, these deficiencies are made up in the teachings of Terpe.
Terpe teaches purifying recombinant proteins comprising incorporating a poly-His tag into the proteins is a “widely employed” method (pages 524-525, in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to incorporate a poly-His tag into the fusion proteins of the combined method because Dimitrov et al envisions “any suitable method” for purifying antigens and Terpe teaches purifying recombinant proteins comprising incorporating a poly-His tag into the proteins is a “widely employed” method. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
In the Reply of 12/3/25, Applicant repeats arguments addressed above.
Claim Rejections – 35 USC § 103
Claim(s) 1, 23, 25-27, 29-31, 35, 36, 38-41, 45, 46, and 48 remain rejected under 35 U.S.C. 103 as being unpatentable over Dimitrov et al (WO 2009/137632 A2; 11/12/09; 3/14/19 IDS) in view of Haynes et al (US 2006/0014148 A1; 1/19/06), Berman et al (Nature, 1990, 345: 622-625), Wibmer et al (PLOS Pathogens, 2017, e1006074; 1-30), and Kovacs et al (PNAS, 2014, 111(52): 18542-18547; 5/27/21 IDS), as applied to claims 1, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 above, and further in view of Tickle et al (JALA, October 2009, 303-307).
Teachings of Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al are discussed above. Dimitrov et al further envisions therapeutic methods of administering antibodies specific for gp41-Fc immunogens (lines 11-14 on page 6, in particular) and methods of screening for antibodies that specifically binds gp41 antigen constructs (lines 28-30 on page 8, in particular).
Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al do not specifically teach a method of screening for an antibody that selectively binds an immunogenic fusion protein of the combined method comprising contacting the immunogenic fusion protein with a plurality of antibodies and identifying an antibody that has a high binding affinity to the fusion protein relative to other antibodies in the composition. However, these deficiencies are made-up in the teachings of Tickle et al.
Tickle et al teaches a method of screening for an antibody that selectively binds a protein comprising contacting the protein with a plurality of antibodies and identifying an antibody that has a high binding affinity to the protein relative to other antibodies in the composition (pages 304-306, in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to screen for an antibody that selectively binds an immunogenic fusion protein of the combined method by performing the method of Tickle et al comprising contacting the immunogenic fusion protein with a plurality of antibodies and identifying an antibody that has a high binding affinity to the fusion protein relative to other antibodies in the composition because Dimitrov et al envisions therapeutic methods of administering antibodies specific for gp41-Fc immunogens (lines 11-14 on page 6, in particular) and methods of screening for antibodies that specifically binds gp41 antigen constructs (lines 28-30 on page 8, in particular) and the method of Tickle et al is a method of screening for an antibody that selectively binds a protein comprising contacting the protein with a plurality of antibodies and identifying an antibody that has a high binding affinity to the protein relative to other antibodies in the composition (pages 304-306, in particular). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
In the Reply of 12/3/25, Applicant repeats arguments addressed above.
Claim Rejections – 35 USC § 103
Claim(s) 1, 7, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 remain rejected under 35 U.S.C. 103 as being unpatentable over Dimitrov et al (WO 2009/137632 A2; 11/12/09; 3/14/19 IDS) in view of Haynes et al (US 2006/0014148 A1; 1/19/06), Berman et al (Nature, 1990, 345: 622-625), Wibmer et al (PLOS Pathogens, 2017, e1006074; 1-30), and Kovacs et al (PNAS, 2014, 111(52): 18542-18547; 5/27/21 IDS), as applied to claims 1, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 above, and further in view of Kim (US 2016/0152726 A1; 6/2/16).
Teachings of Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al are discussed above. Dimitrov et al further teaches immunogenic fusion proteins comprising Fc regions that are variants 80%, 85%, 90%, 95% or 99% identical to SEQ ID NO: 5 of Dimitrov et al (lines 1-4 on page 6, in particular).
Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al do not specifically teach an immunogenic fusion protein with an Fc domain comprising instant SEQ ID NO:77. However, these deficiencies are made-up in the teachings of Kim et al.
Kim et al teaches numerous Fc domains, including SEQ ID NO:6 (“Mouse IgG2aa”) that is 100% identical to instant SEQ ID NO:77 (Figure 4 and [0031], in particular). It further appears the Human IgG1 Fc domain of Kim et al is 100% identical to SEQ ID NO: 5 of Dimitrov et al (compare Human IgG1 Figure 4 of Kim et al and Figure 10 of Dimitrov et al, in particular). SEQ ID NO:6 (“Mouse IgG2aa”) of Kim et al is an Fc region that is a variant 80%, 85%, 90%, 95% or 99% identical to SEQ ID NO: 5 of Dimitrov et al.
One of ordinary skill in the art would have been motivated, with an expectation of success, to generate immunogenic fusion protein of the combined method with an Fc domain comprising instant SEQ ID NO:77 because Dimitrov et al teaches immunogenic fusion proteins comprising Fc regions envisioned by Dimitrov et al include variants 80%, 85%, 90%, 95% or 99% identical to SEQ ID NO: 5 of Dimitrov et al (lines 1-4 on page 6, in particular) and Kim et al teaches an Fc region identical to instant SEQ ID NO:77 that is a variant 80%, 85%, 90%, 95% or 99% identical to SEQ ID NO: 5 of Dimitrov et al. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
I In the Reply of 12/3/25, Applicant repeats arguments addressed above.
Claim Rejections – 35 USC § 103
Claim(s) 1, 23, 25-27, 29, 31, 35, 36, 38-41, 44, 45, 46, and 48 remain rejected under 35 U.S.C. 103 as being unpatentable over Dimitrov et al (WO 2009/137632 A2; 11/12/09; 3/14/19 IDS) in view of Haynes et al (US 2006/0014148 A1; 1/19/06), Berman et al (Nature, 1990, 345: 622-625), Wibmer et al (PLOS Pathogens, 2017, e1006074; 1-30), and Kovacs et al (PNAS, 2014, 111(52): 18542-18547; 5/27/21 IDS), as applied to claims 1, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 above, and further in view of Ma et al (Vaccine, 2014, 32: 6170-6176) and Vuyisich et al (Protein J, 2008, 27: 292-302).
Teachings of Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al are discussed above.
Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al do not specifically teach a leader peptide/signal sequence comprising instant SEQ ID NO:84. However, these deficiencies are made up in the teachings of Ma et al and Vuyisich et al.
Ma et al teaches the leader peptide/signal sequence IL2ss fused to recombinant polypeptides directs secretion of the recombinant polypeptides into culture supernatants (Figure 1, in particular).
Vuyisich et al teaches IL2ss as a sequence 100% identical to SEQ ID NO:84 (compare IL2ss at right column on page 294 with instant SEQ ID NO:84, in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to generate fusion proteins of the combined method wherein the leader peptide/signal sequence comprises IL2ss because Dimitrov et al envisions purifying generated fusion proteins from culture supernatants and IL2ss is a leader peptide/signal sequence that is fused to recombinant polypeptides in order to direct secretion of the recombinant polypeptides into culture supernatants. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
In the Reply of 12/3/25, Applicant repeats arguments addressed above.
Claim Rejections – 35 USC § 103
Claim(s) 1, 23, 25-27, 29, 31, 35, 36, 38-41, and 45-48 remain rejected under U.S.C. 103 as being unpatentable over Dimitrov et al (WO 2009/137632 A2; 11/12/09; 3/14/19 IDS) in view of Haynes et al (US 2006/0014148 A1; 1/19/06), Berman et al (Nature, 1990, 345: 622-625), Wibmer et al (PLOS Pathogens, 2017, e1006074; 1-30), and Kovacs et al (PNAS, 2014, 111(52): 18542-18547; 5/27/21 IDS), as applied to claims 1, 23, 25-27, 29, 31, 35, 36, 38-41, 45, 46, and 48 above, and further in view of Baldo (Drug Saf, 2015, 38: 455-479).
Teachings of Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al are discussed above.
Dimitrov et al, Haynes et al, Berman et al, Wibmer et al, and Kovacs et al do not specifically teach whether the “gp140-FL20” of Fig 1 of Kovacs et al of the fusion construct of the combined method (comprising gp120 linked via a non-HIV sequence 20-amino acid linker to gp41) is N-terminal or C-terminal to the Fc domain of the fusion construct of the combined method. However, these deficiencies are made up in the teachings of Baldo.
Like Dimitrov et al and Haynes et al, Baldo teaches Fc domains of fusion proteins provide the benefit of extending half lives of the fusion proteins (left column on page 455, in particular). Baldo further teaches Fc domains of fusion proteins can be N-terminal or C-terminal to other polypeptides o the fusion proteins (left column of page 455, Figure 1, and Figure 7, in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to perform the combined method wherein the “gp140-FL20” of Fig 1 of Kovacs et al of the fusion construct of the combined method (comprising gp120 linked via a non-HIV sequence 20-amino acid linker to gp41) is either N-terminal or C-terminal to the Fc domain of the fusion construct of the combined method because Baldo further teaches Fc domains of fusion proteins can be N-terminal or C-terminal to other polypeptides o the fusion proteins (left column of page 455, Figure 1, and Figure 7, in particular). This is an example of “choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success”. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
In the Reply of 12/3/25, Applicant repeats arguments addressed above.
Allowable Subject Matter
Claims 42-43 remain objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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