DETAILED ACTION
Disposition of Claims
Claims 94-97, 100, 102, 106-110, and 115-123 were pending. Claims 1-93, 95-105, 108, 111-117, and 121 have been cancelled. Amendments to claims 94, 106-107, 109, 118-120, and 122 are acknowledged and entered. New claims 124-133 are acknowledged and entered. Claims 94, 107, 109-110, and 118-120, and 122-133 will be examined on their merits.
Examiner’s Note
Unless otherwise noted, the paragraph numbers reference the PGPub of the instant application, US20240270796A1, Pub. 08/15/2024.
Response to Arguments
Applicant's arguments filed 10/22/2025 regarding the previous Office action dated 06/23/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 114-115 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 94, 109, and 120 and dependent claims 95-97, 100, 102, 106-108, 110, 115-119, and 121-123 thereof under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 94 is drawn to an antigenic composition of human cytomegalovirus (HCMV) polypeptides, comprising:
a glycoprotein H (gH)/glycoprotein L (gL) heterodimer (gH/gL heterodimer), wherein the gH comprises an extracellular domain and wherein the gH/gL heterodimer is a recombinant fusion protein;
a unique long 128 (UL128) polypeptide, a unique long 130 (UL130) polypeptide and a unique long 131A (UL131A) polypeptide; and
a glycoprotein B (gB), wherein the gB comprises an extracellular domain and wherein the gB is trimeric.
Further limitations on the antigenic composition of claim 94 are wherein the gH/gL heterodimer is monomeric (claim 95); wherein the gH/gL heterodimer is multimeric (claim 96), namely trimeric (claim 97); wherein the UL128, UL130 and UL131A polypeptides are in a recombinant fusion protein (claim 100); wherein the gH/gL heterodimer, and the UL128, UL130 and UL131A polypeptides are in a protein complex (claim 102); wherein a furin recognition site in the gB is removed (claim 106); further comprising a glycoprotein M (gM), glycoprotein N (gN), or a combination thereof (claim 107); wherein the gH/gL heterodimer and the UL128, UL130, and UL131A polypeptides are comprised within one or more virus like particles (claim 108); wherein the gH/gL heterodimer, and the UL128, the UL130, and the UL 131A polypeptides are not comprised within a virus-like particle (claim 115); 116. (New) The antigenic composition of claim 94, wherein: the gH/gL heterodimer is monomeric, and the UL128, UL130 and UL131A polypeptides are in a monomeric protein complex (claim 116), wherein a furin recognition site in the gB is replaced by a linker sequence (claim 117), and wherein the linker sequence comprises glycine and serine amino acids and has a length of 10-25 amino acids (claim 118).
Claim 109 is drawn to a composition of nucleic acids encoding human cytomegalovirus (HCMV) polypeptides, comprising:
a nucleic acid encoding a glycoprotein H (gH)/glycoprotein L (gL) heterodimer(gH/gL heterodimer), wherein the gH comprises an extracellular domain and wherein the gH/gL heterodimer is a recombinant fusion protein;
one or more nucleic acids encoding UL128, UL130 and UL131 polypeptides; and
a nucleic acid encoding a glycoprotein B (gB), wherein the gB comprises an extracellular domain and forms a trimeric gB when expressed in a host cell.
Further limitations on the composition of claim 109 are wherein a furin recognition site in the gB is replaced by a linker sequence (claim 119).
Claim 110 is drawn to a method for inhibiting or treating an HCMV infection in a subject, comprising administering a therapeutically effective amount of the antigenic composition of claim 94 to a subject.
Claim 120 is drawn to an antigenic composition of human cytomegalovirus (HCMV) polypeptides, comprising:
a monomeric heterodimer of a HCMV glycoprotein H (gH) polypeptide and a HCMV glycoprotein L (gL) polypeptide (gH/gL heterodimer), wherein the HCMV gH polypeptide comprises an extracellular domain and wherein the gH/gL heterodimer is a recombinant fusion protein;
a monomeric protein complex comprising an HCMV unique long 128 (UL128) polypeptide, an HCMV unique long 130 (UL130) polypeptide, and an HCMV unique long 131A (UL131A) polypeptide (monomeric UL128/UL130/UL131Aconstruct); and
a trimeric HCMV glycoprotein B (gB) polypeptide, wherein the HCMV gB polypeptide comprises an extracellular domain.
Further limitations on the antigenic composition of claim 120 are wherein the monomeric UL128/UL130/UL131A construct is a recombinant fusion protein (claim 121), wherein a furin recognition site in the gB is replaced by a linker sequence, the linker sequence comprising glycine and serine amino acids and having a length of 10-25 amino acids (claim 122), and wherein the linker sequence comprises the amino acid sequence of SEQ ID NO: 3 (claim 123).
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 94-97, 100, 102, 106-107, 109-110, and 115-123 under 35 U.S.C. 103 as being unpatentable over Carfi et. al. (US20160159864A1, Pub. 06/09/2016; CITED ART OF RECORD; hereafter “Carfi”) and Carfi et. al. (WO2016092460A2, Pub. 06/16/2016; CITED ART OF RECORD; hereafter “Carfi-460”);
in view of Mond et. al. (US20150174237A1; Pub. 06/25/2015; CITED ART OF RECORD; hereafter “Mond”); and
Kabanova et. al. (Kabanova A, et. al. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):17965-70. Epub 2014 Dec 1.; hereafter “Kabanova”) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claim 108 under 35 U.S.C. 103 as being unpatentable over Carfi and in view of Carfi-460, Kabanova, and Mond as applied to claims 94-97, 100, 102, 106-107, 109-110, and 115-123 above, and further in view of Wellnitz et. al. (US20150359879A1, Pub. 01/30/2014; CITED ART OF RECORD; hereafter “Wellnitz”) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 94, 107, 109-110, and 118-120, and 122-133 are rejected under 35 U.S.C. 103 as being unpatentable over Orlinger et. al. (US20160296619A1; Pub. 10/13/2016; hereafter “Orlinger”) and
Carfi et. al. (US20160159864A1, Pub. 06/09/2016; CITED ART OF RECORD; hereafter “Carfi”); and in view of
Mond et. al. (US20150174237A1; Pub. 06/25/2015; CITED ART OF RECORD; hereafter “Mond”);
Shenk et. al. (US20080187545A1, Pub. 08/07/2008; hereafter “Shenk”.)
Kong et. al. (WO2017192434A1, Priority 05/02/2016; hereafter “Kong”);
Cui et. al. (WO2015089340A1; Pub. 06/18/2015; hereafter “Cui”);
Kabanova et. al. (Kabanova A, et. al. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):17965-70. Epub 2014 Dec 1.; hereafter “Kabanova”); and
Spaete et. al. (US6190860B1, Iss 02/20/2001; hereafter “Spaete”.)
The Prior Art
Orlinger teaches pharmaceutical compositions, vaccines, and methods of treating cytomegalovirus (CMV) infections and reactivation (entire document; see abstract.) Orlinger teaches vectors which encode CMV proteins, namely CMV gB, gH, gL, UL128, UL130, and UL131A (reference claim 1), as pentameric complex formed by the glycoproteins gH/gL (UL75/UL115), UL128, UL130, and UL131A is required for HCMV entry into epithelial and endothelial cells and is the target of potent neutralizing antibodies in HCMV-seropositive individuals (¶[0014]). Orlinger teaches the gB protein was tested as a CMV vaccine candidate as it comprises dominant targets of neutralizing antibodies (¶[0013]). Orlinger teaches that ser/gly linkers can separate the open reading frames (ORFs) of the CMV proteins (¶[0242]), and that the compositions comprise either the nucleic acids encoding said proteins or fusion proteins of the CMV proteins described (¶[0080]). Orlinger teaches the fusion proteins may be of the CMV proteins and comprise two, three, four, five, six, or seven total antigens fused to heterologous sequences (¶[0290]). Orlinger teaches the gH may be deleted for the transmembrane domain and thus only comprise the extracellular domain (Fig. 3; ¶[0266][0521]), and that the CMV glycoproteins gH and gL are typically associated with one another (¶[0014][0520]). Orlinger also teaches the CMV gB would have the transmembrane and cytoplasmic domains deleted (¶[0421][0531]; reference claim 27) and in at least one embodiment substituted with a heterologous polypeptide (reference claim 21). Orlinger teaches the removal of the furin cleavage site located within the ectodomain of gB (Fig. 2; ¶[0150][0518]; instant claim 106). Orlinger teaches methods of inducing an immune response against CMV through administration of the compositions comprising the vector or proteins encoded thereof (reference claims 54, 88-89; ¶[0336][0339-0381]; instant claim 110).
Carfi teaches an isolated human cytomegalovirus (HCMV) membrane protein complex, wherein said complex comprises gH, gL, UL128, UL130, and UL131A proteins, and methods for expressing and purifying said protein complexes (entire document; see abstract.) Carfi teaches that said purified complexes can be used in immunogenic compositions and vaccines (entire document; see abstract.) Carfi teaches the pentameric complex may be monomeric (¶[0290]) or that gH/gL heterodimers or heteromultimers may be formed (¶[0009]), wherein gH/gL may form a heterotrimer with gO (abstract), wherein gH/gL inherently associates with either gO to form a trimer or with the UL128/UL130/UL131A trimer to form a pentameric complex (¶[0005][0105].) Carfi teaches additional glycoproteins from HCMV may be present, such as glycoprotein B (gB) (¶[0047-0053]). Carfi teaches the gH glycoprotein comprises a C-terminal cytoplasmic domain, but that the transmembrane (TM), cytoplasmic, and N-terminal signal sequence may be removed from the gH protein (¶[0026-0027]). Carfi teaches the polypeptide antigens may be fusion polypeptides (¶[0110]), and that the nucleic acid encoding the HCMV proteins may be delivered via virus-like particles (VLPs)(¶[0107]). Carfi teaches vaccine compositions comprising the isolated pentamer, wherein said vaccine is administered in a therapeutically effective amount to inhibit HCMV infection (¶[0105-0110]; reference claim 47; instant claim 110). Carfi teaches sequences for the CMV proteins which are identical to those of the instant claims (for alignments, see attached NCBI BLAST for US Pat. No. 9,683,022):
CMV
Protein
Instant
SEQ ID NO:
Carfi
SEQ ID NO:
%
Identity
gH
17
3
100
gL
18
7
100
UL128
23
14
100
UL130
24
16
100
UL131A
25
18
100
While Orlinger and Carfi combined teach the majority of the instantly claimed invention, and teach that the CMV pentameric proteins may be fused to one another, such as Carfi teaches the HCMV trimer and pentameric proteins may be fusion polypeptides, neither Orlinger nor Carfi explicitly teach wherein the gH/gL proteins or wherein the three UL128/UL130/UL131A proteins are joined as singular recombinant fusion proteins. However, such optimization would be obvious to a skilled artisan, given the teachings of Mond and Shenk. Additionally, while Orlinger teaches the gB furin site may be cleaved, Orlinger fails to teach said mutation is the result of the gB furin site being replaced by a flexible ser/gly linker. While Orlinger and Carfi teach a number of gB sequences are known in the art, and both teach at least one sequence for gB, neither Orlinger nor Carfi appear to teach instant SEQ ID NO: 19. However, HCMV gB variants for use in vaccine studies were well-known in the art, and motivation to combine both subunit HCMV pentameric complexes (PCs) and HCMV gB was also present in the art, as evidenced by Kabanova and Spaete. Further, replacing a glycoprotein furin cleavage site with a flexible linker to ensure the resulting protein generated the most immunogenically relevant form of the protein was also known in the art, as evidenced by the teachings of Cui and Kong.
Mond teaches fusion proteins that incorporate unique mechanisms for multimerizing antigens to enhance their immunogenicity (entire document; see abstract). Mond teaches fusion proteins which comprise a first antigen, a linker sequence, a second antigen, and an oligomerization domain (reference claim 1), wherein the first and second antigens are viral antigens (reference claim 3) from cytomegalovirus (CMV)(reference claim 5) and include gB, gH, and gL antigens (reference claim 7; ¶[0047-0048][0059]). Mond teaches that CMV homodimers or homotrimers of gB, gL, gH, or pp65 may be generated, or that antigens from gB may be fused using the linkers, or heterodimers of gL and gH may be generated (¶[0047]). Mond teaches the linker sequence is a polypeptide of 5-25 amino acids comprising glycine and serine amino acids, preferably a (Gly4 Ser)3 linker (¶[0087]; SEQ ID NO:3; which is 100% identical to instant SEQ ID NO: 3; instant claims 118, 123, 125, 127). Mond teaches the generation of an Epstein-Barr virus (EBV) gH/gL fusion protein heterodimer with a trimerization domain, wherein the gH/gL heterodimer is involved in cell attachment/fusion in EBV and other herpesviruses, such as CMV, as noted by Mond (Example 10 at ¶[0147][0073]). Mond teaches the engineered herpesvirus proteins comprised an IgGκ leader sequence to facilitate protein secretion, as well as the use of (Gly4Ser)3 flexible linkers to allow for proper protein folding (¶[0119][0134]; instant claims 128-133). Mond teaches multimerization of herpesvirus surface glycoproteins can confer increased immunogenicity, which is why they engineered a DNA construct that would direct the production of a native formation of tetrameric Epstein-Barr virus (EBV) gp350. Mond teaches that EBV neutralizing antibody, required for a successful prophylactic vaccine, is specific for the conformational epitope of gp350 that mediates binding to CD21 on human B cells, mediating EBV entry. Thus, proper folding of the individual gp350 molecules in the tetramer was considered important (¶[0134]).
Shenk teaches immunogenic compositions and prophylactic or therapeutic vaccines for use in protecting and treating against human cytomegalovirus (CMV), wherein the immunogenic compositions are subunit vaccines comprising a human CMV protein complex comprising pUL128 or pUL130, and nucleic acid vaccines comprising at least one nucleic acid encoding a CMV protein complex comprising pUL128 or pUL130 (entire document; see abstract; instant claim 110.) Shenk teaches the vaccine can be constructed to express one or more proteins involved in the UL128-UL130 complex, and would include one or more of UL128, UL130, UL131, gH, gL, or gB, especially wherein two or more of such proteins are within a single polypeptide (¶[0019][0089]; reference claims 9-11).
Kabanova teaches a CMV pentamer protein subunit vaccine and the antibodies generated therefrom (entire document; see abstract.) Kabanova teaches expression of intronless, full-length UL128, UL130, UL131, gH (deprived of the transmembrane portion and the cytoplasmic domains), gL, and gO of CMV strain VR1814 were cloned into pcDNA3 vectors, along with soluble gB generated as a truncated ectodomain (amino acids 1–690, accession no. ACZ79977)(p. 17969, “Materials and Methods: Protein Expression by Transient Transfection of 293F Cells.”) In CHO cells, the pentameric proteins were expressed from a single polycistronic vector, wherein each protein was separated by a 2A site, and the signal peptide of gH was replaced with an IgG leader sequence (p. 17969, “Materials and Methods: Expression of the gHgLpUL128 Pentamer in CHO Cells.”) Kabanova teaches that the pentamer-specific antibodies produced by infected humans or immunized mice were neutralizing, indicating that this antigen has the capacity to induce an antibody response of high specific activity, while only a small fraction of those antibodies produced in gB-vaccinated persons had neutralizing activity. Kabanova teaches it may be due to utilizing the wrong form of gB, as it appears to be in a metastable state in a pre- and post-fusion conformation, and that the post-fusion conformation may not be eliciting the most important antigenic response. Kabanova teaches it would be important to generate a prefusion form of gB, and it would likely be ideal to vaccinate a person with both the CMV pentamer complex and prefusion form of gB (p. 17969, left col., ¶2-3).
Kong teaches viral surface glycoprotein immunogens, namely from HIV gp140 (entire document; see abstract.) Kong teaches that in gp140, studies were performed to remove the native cleavage sites and replace them with short, flexible linkers to allow for the formation of structures such as trimers (¶[0093]). Kong teaches replacing the furin cleavage site of gp140 with a ser/gly linker of different lengths (Examples 5-6 at ¶[0093-0099]). While Kong noted that longer linkers, such as a (G4S)x2 linker, could reduce the formation of fusion intermediates, this was likely at the cost of greater conformational variability. However, it was noted the prefusion form was immunogenically preferable, likely to aid in prevention of viral attachment to the target cell (¶[0097]).
Similarly, Cui teaches modified herpesvirus gB proteins, wherein they insert a peptide linker at the furin cleavage site in the extracellular domain of herpesvirus gB. When expressed, the gB subunit associates in triplicate to produce a homotrimeric complex, mimicking the native conformation of the gB protein (entire document; see abstract.) Cui teaches the use of (Gly4Ser)3 linkers inserted into the furin cleavage site, wherein the ser/gly linker is 15 aa in length (¶[0059]). Cui teaches this may be done with any of the known herpesvirus gB proteins, including HCMV (¶[0058]).
Spaete teaches recombinant polypeptides derived from CMV glycoprotein gB and truncated fragments thereof which contain at least one epitope which is immunologically identifiable with one encoded by the CMV genome (entire document; see abstract.) Spaete teaches SEQ ID NO: 9 as a sequence for gB, which is 100% identical to instant SEQ ID NO: 19. Spaete teaches modification of the known endoproteolytic cleavage site of gB (Table 2, Fig. 2; Cols. 2-3, ¶ bridging cols.)
Given the teachings of Orlinger and Carfi, a skilled artisan would be apprised as to the generation of subunit vaccine compositions comprising the most immunogenically relevant CMV proteins, namely gB and those proteins which form the CMV pentamer (gH, gL, UL128, UL130, and UL131A), as well as compositions which comprised the nucleic acids encoding said proteins. Given the teachings of Orlinger and Spaete, a skilled artisan would be motivated to mutate the furin cleavage site in gB, but also given further motivation from the prior art, one way of performing this mutation while allowing the gB to form its native trimers would be to use (G4S)x2 flexible linkers, as suggested by Kong and Cui. Given further teachings and motivation by the art, a skilled artisan would be apprised as to the usefulness of a CMV pentamer and gB combination subunit vaccine, especially one wherein the proteins may be expressed as singular units or fusion proteins in order to assist formation of their native conformation, as suggested by Orlinger, Carfi, Kabanova, Shenk, Cui, and Mond. Given the teachings of Mond, a skilled artisan would be apprised as to the usefulness of generating some of these naturally multimeric proteins as fusion proteins specifically to increase their immunogenicity, such as generating a fusion protein from CMV gH/gL proteins or fusion proteins of other antigens or members of the HCMV pentamer. As Shenk and Carfi teach the signal peptides on these glycoproteins are removed before maturation of the glycoprotein (Shenk ¶[0036]; Carfi ¶[0027-0028]), and Kabanova and Mond teach the use of heterologous leader sequences (such as IgK leader sequences) to aid in easier isolation of the protein from cell production systems, the use of such modifications to the CMV proteins would be obvious to aid in purification. Given the teachings of Mond, which teach flexible ser/gly linkers in the herpesvirus proteins, and given the teachings of Kong and Cui, which teach the specific use of these ser/gly linkers to replace furin cleavage sites in viral glycoproteins to aid in generating structurally relevant proteins, such as HCMV gB as taught by Cui, it would be further obvious to arrive at the overall constructs of the instant claims. Given the known sequences of these proteins, as evidenced by the teachings of Spaete and Carfi, a skilled artisan would be apprised as to specific sequences for these proteins, and given the guidance from Carfi, one would be apprised as to the location of the N-terminal native peptide signal sequences for these proteins which are typically cleaved upon protein maturation. Taken as a whole, given what was known in the art at the time of filing, as evidenced by Orlinger, Carfi, Mond, Shenk, Kabanova, Cui, Kong, and Spaete, the limitations of instant claims 94, 107, 109-110, and 118-120, and 122-133 would be obvious constructs, compositions, and methods for a skilled artisan with respect to CMV vaccine development.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Orlinger and Carfi in order to generate gH and gL as fusion proteins to one another joined by a flexible linker, thereby increasing the stability and immunogenicity of this complex, and likewise to generate a fusion protein from UL128/UL130/UL131 proteins. Further, skilled artisans would be apprised as to the important surface glycoproteins that should be included in a subunit vaccine composition against CMV, including gB, gM, gN, and gH/gL within the pentamer complex, as taught by Orlinger, Carfi, Spaete, Shenk, and Kabanova. One would have been motivated to do so, given the suggestion by Mond that CMV glycoproteins, such as gH and gL, could be fused to each other to increase the stability of this heterodimer important in many CMV complexes, and given that Mond teaches the Ser/Gly linker of the instant invention and that antigens from CMV proteins, such as gB, can be fused to each other using said linkers. There would have been a reasonable expectation of success, given the knowledge that gH and gL are an important part of the CMV pentamer and other complexes, as taught by Orlinger, Carfi, Spaete, Shenk, Kabanova, and Mond, and also given the knowledge that joining gH and gL glycoproteins increases the immunogenicity and stability of these proteins, as taught by Mond. There would have been further reasonable expectation of success in mutating the gB protein, as suggested by Spaete and Orlinger, by introducing a flexible linker into the furin cleavage site to allow for proper 3D formation of the mature protein to generate a more immunogenic construct, as suggested by Kong, and to specifically insert the (Gly4Ser)3 linker into the furin cleavage site, as taught by Cui. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant’s arguments, see “Remarks”, filed 10/22/2025, with respect to the rejection of the claims under 35 USC 103 have been fully considered and are persuasive in light of the amendments to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejection are made using the teachings of Carfi, Mond, and Kabanova (detailed supra.) Arguments presented regarding Carfi, Kabanova, and Mond will be addressed as applicable herein in the interest of compact prosecution.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Carfi fails to teach the use of gB along with the proteins which make up the CMV pentamer. Carfi teaches that gB interacts with gH and has implications in activation of membrane fusion (¶[0025]) and then specifically mentions that their invention encompasses an immune composition comprising HCMV complexes, wherein the complex comprises a complex that has gH/gL, such as the gH/gL/UL128/UL130/UL131A pentameric complex, and notes that said composition may additionally comprise other HCMV proteins (but preferably not non-envelope HCMV proteins) such as glycoprotein B (gB)(¶[0047]). Therefore, it is unclear how Carfi fails to teach or suggest gB as being in an immunogenic composition with the pentameric proteins. If Applicant is referencing the limitations of instant claim 120, it is respectfully noted that the claim utilizes open-ended claim language (“comprising”) which allows for the inclusion of additional, unrecited elements. If this is a point of novelty, it should be clearly claimed as such (e.g. through the use of close-ended transitional phrases or language.) Additionally, the language of the other references cited herein (see e.g. Orlinger ¶[0067][0440-0455]; Mond reference claim 7, ¶[0047][0059]; Shenk ¶[0012]) allows for one of skill to at once envisage a limited number of possible CMV protein combinations, including gH, gL, and gB. Therefore, taken as a whole and especially in light of the newly presented art teachings, such an argument is not persuasive.
Applicant further argues that one of skill in the art would not have had a reasonable expectation of success given the art-recognized problem of vaccine or immune interference. Such an argument does not appear to hold substantial weight as the majority of references cited herein explicitly recommend not only the use of all five pentamer proteins, but specifically to combine said proteins with the additional surface protein gB. Immunization with a combination of these HCMV envelope proteins not only provides broader protection to cover potentially all the HCMV target cells, it also markedly enhances the HCMV neutralizing activities elicited compared to individual envelope proteins or protein complexes. Immunization with individual envelope protein trimeric HCMV gB, HCMV gH/gL or UL128/UL130/UL131A each induced high serum titers of antigen-specific IgG, and immunization with various combinations of these proteins did not lead to interference in the induction of individual antigen-specific IgG responses, consistent with the findings of other investigators (See e.g. McVoy MA, et. al. Vaccine. 2015 Dec 16;33(51):7328-7336. Epub 2015 Oct 24.; See also post-filing art Chiuppesi F, et. al. J Virol. 2018 Sep 12;92(19):e01012-18. Erratum in: J Virol. 2019 Nov 13;93(23):e01557-19.) The Examiner wishes to inform applicants of the following guidelines pertaining to arguments that mirror supported claims or facts but are not founded on a factual basis.
In the MPEP:
MPEP §2145 Consideration of Applicant's Rebuttal Arguments:
(I) ARGUMENT DOES NOT REPLACE EVIDENCE WHERE EVIDENCE IS NECESSARY
Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and§ 2144.03 for a discussion of admissions as prior art.
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602,145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
MPEP §716.01 (c) Probative Value of Objective Evidence
I. TO BE OF PROBATIVE VALUE, ANY OBJECTIVE EVIDENCE SHOULD BE SUPPORTED BY ACTUAL PROOF
Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ191, 196 (Fed. Cir. 1984) (“It is well settled that unexpected results must be established by factual evidence.” “[A]ppellants have not presented any experimental data showing that prior heat-shrinkable articles split. Due to the absence of tests comparing appellant’s heat shrinkable articles with those of the closest prior art, we conclude that appellant’s assertions of unexpected results constitute mere argument.”). See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356,358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058(Bd. Pat. App. & Inter. 1991).
II. ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCE
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602,145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant.
See MPEP § 2145 generally for case law pertinent to the consideration of applicant’s rebuttal arguments.
III. OPINION EVIDENCE
Although factual evidence is preferable to opinion testimony, such testimony is entitled to consideration and some weight so long as the opinion is not on the ultimate legal conclusion at issue. While an opinion as to a legal conclusion is not entitled to any weight, the underlying basis for the opinion may be persuasive. In re Chilowsky,306 F.2d 908, 134 USPQ 515 (CCPA 1962) (expert opinion that an application meets the requirements of 35U.S.C. 112 is not entitled to any weight; however, facts supporting a basis for deciding that the specification complies with 35 U.S.C. 112 are entitled to some weight); In re Lindell, 385 F.2d 453, 155 USPQ 521 (CCPA 1967)(Although an affiant’s or declarant’s opinion on the ultimate legal issue is not evidence in the case, “some weight ought to be given to a persuasively supported statement of one skilled in the art on what was not obvious to him.” 385 F.2d at 456, 155 USPQ at 524 (emphasis in original)).
Presently and in view of the guidance from MPEP §2145 and §716 above, Applicants statements regarding it is well recognized in the art that antigens can elicit immunogenic interference in vaccine compositions and a skilled artisan would not have a reasonable expectation of success in combining the CMV pentamer complex with gB is not supported by any factual evidence, either information/data from applicant’s specification, or the state of the art relating to CMV gB and gH/gL/UL128/UL130/UL131A vaccination studies. Therefore, this line of argument is not persuasive.
Applicant further argues unexpected and/or surprising results. However, such “unexpected” or “surprising” results are not commensurate in scope with the breadth of the claims as presently claimed. The breadth of possible antigens (e.g. any HCMV gH polypeptide or mutant, fusion protein, or fragment thereof comprising any extracellular domain – note the breadth of the claim does not require the extracellular domain to be from HCMV gH; any HCMV gL polypeptide, mutant, or fragment thereof, wherein the gH and gL are fused in any combination to one another; any HCMV gB protein, so long as said gB is able to generate a homotrimer and comprises “an extracellular domain” – again the breadth of the claims does not require the extracellular domain to be from HCMV gB; any recombinant fusion protein comprising, in any order, any HCMV UL128 sequence, mutant, or fragment thereof, any HCMV UL130 sequence, mutant, or fragment thereof, and any HCMV UL131 sequence, mutant, or fragment thereof) is not reasonably recognized by the limited examples provided for in the specification. Those gH/gL fusion proteins utilized specific HCMV gH and gL sequences; a gL sequence encoding amino acids 31-278 was used, and the signal peptide corresponding to amino acids 1-30 was replaced with an IgG κ leader sequence. The gH sequence encoding amino acids 24-718 was linked to the 3′ end of gL and separated by a 15-amino acid linker (Gly4Ser)3 (SEQ ID NO: 3) sequence. A foldon trimerization domain coding sequence derived from T4 phage fibritin was linked to the 3′ end of gH, followed by a His6 (SEQ ID NO: 49) coding sequence for protein purification for the trimeric version of gH/gL The monomeric HCMV gH/gL construct was made by PCR amplification of the trimeric HCMV gH/gL without the foldon trimerization domain coding sequence (¶[0296]). The HCMV gB comprised a specific extracellular domain of HCMV gB which lacked the N-terminal signal peptide and was replaced with an IgK leader sequence, wherein the furin cleavage site of gB was replaced with a 15-amino acid ser/gly linker (G4S)x3 (¶[0276]). As noted by Applicant, one cannot use just any sequence for the UL128/UL130/UL131A sequences, as these are often mutated in laboratory strains of HCMV, which alters the viral tropism and renders the proteins non-functional (¶[0305]). Therefore, specific, wild-type sequences for UL128, UL130, and UL131A were carefully chosen, and the construct was generated as follows: the UL128 sequence encoding amino acids 28-171, UL130 sequence encoding amino acids 26-214, and UL131A sequence encoding amino acids 19-129, were linked by a 15-amino acid linker (Gly4Ser)3 (SEQ ID NO: 3) between each coding sequence (FIG. 10 ). A foldon trimerization domain coding sequence derived from T4 phage fibritin was linked to the 3′ end of UL131A, followed by a His6 (SEQ ID NO: 49) coding sequence, and an IgGκ leader sequence was placed 5′ to the UL128 sequence for secretion of recombinant protein (FIG. 10 )(¶[0305]).
Therefore, the breadth of the instant claims is certainly not commensurate in scope with the specific constructs, sequences, and conditions which were tested. It is not clear as to the criticality of the parameters for each protein as to what provided the surprising and/or unexpected results. While Applicant notes synergistic results and points to that as evidence of non-obviousness, it remains that the large breadth and possible combinations of the instant claims are not encompassed by the conditions which provided the synergistic results. As the scope of the claims is not reasonably represented by the limited examples, such an argument is not convincing.
For at least these reasons, the claims as amended are still obvious over the prior art, and the arguments presented were unconvincing as to the claims being non-obvious.
Double Patenting
The text regarding nonstatutory double patenting (NSDP) was presented in a previous Office action.
(Rejection withdrawn.) The rejection of Claims 94-97, 100, 102, 106-110, and 115-123 on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 9,907,844 in view of Carfi, Carfi-460, Kabanova, and Mond (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 94-97, 100, 102, 106-110, and 115-123 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-10, and 15-17 of U.S. Patent No. 9,962,436 in view of Carfi, Carfi-460, Kabanova, and Mond (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 94-97, 100, 102, 106-110, and 115-123 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, and 8-15 of U.S. Patent No. 10,821,173 in view of Carfi, Carfi-460, and Kabanova (supra) is withdrawn in light of the amendments to the claims.
(New rejection – necessitated by amendment.) Claims 94, 107, 109-110, and 118-120, and 122-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S. Patent No. 9,907,844 in view of Orlinger, Carfi, Mond, Shenk, Kabanova, and Spaete (supra.) Although the claims at issue are not identical, they are not patentably distinct from each other because both claimed inventions are drawn towards compositions comprising HHV proteins, namely hCMV gB, that are monomeric multimers or fusion proteins with specific peptide linkers which remove the furin cleavage site from gB. Both claim identical ser/gly linkers inserted into the gB. Both claim said protein composition may comprise gH/gL, UL128, UL130, UL131, and can be within a pharmaceutically acceptable carrier. Both claim said protein may be used in methods to inhibit the cognate HHV infection or inducing immunity against the cognate HHV. The main difference is that the instant claims require the CMV gH/gL to be fused to each other, with the use of specific constructs of gH, but such limitations would be obvious in light of the teachings of Carfi, Orlinger, Kabanova, Spaete, Shenk, and Mond (detailed supra.) As Shenk, Orlinger, Carfi, and Mond render obvious the use of fused polyproteins, such as gH and gL from CMV fused to one another to increase stability and immunogenicity, this would be an obvious optimization to the teachings of the ‘844 claims. Carfi, Orlinger, and Kabanova render obvious the different forms of gH, and why a skilled artisan would be motivated to combine the trimeric gB of the instant and ‘844 claims with the CMV pentamer complex. Carfi and Spaete render obvious the specific sequences for gH, gL, UL128, UL130, UL131, and gB. For at least these reasons, the instant claims and the ‘844 claims are obvious variants of one another, especially in light of the teachings of Carfi, Orlinger, Kabanova, Spaete, Shenk, and Mond, and are not patentably distinct.
Orlinger, Carfi, Mond, Shenk, Kabanova, Cui, Kong, and Spaete
(New rejection – necessitated by amendment.) Claims 94, 107, 109-110, and 118-120, and 122-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-10, and 15-17 of U.S. Patent No. 9,962,436 in view of Carfi, Orlinger, Kabanova, Shenk, Cui, Spaete, and Mond (supra.) Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to compositions comprising hCMV proteins, namely HCMV proteins gH, gL, and gB, wherein said proteins are expressed as multimers in fusion proteins along with other related viral proteins which also form multimers with themselves, other proteins, or the fusion protein itself. Both sets of claims are drawn to wherein the fusion protein is chosen from a combination of at least two CMV antigens, including gH and gL. Both claim the proteins are joined by linkers. The main difference between the instant claims and the ‘436 claims is that the ‘436 claims are drawn to the antigens forming a multimerization complex in a cell and provide a specific oligomerization domain to the fusion protein, while the instant claims provide for the specific complex proteins, namely gH, gL, UL128, UL130, and UL131A (pentameric complex or PC), and for gB, which forms a multimeric complex with itself and interacts with the PC, wherein gH-gL are a fusion protein and UL128-UL130-UL131 are a fusion protein. Further, the instant claims require replacement of the gB furin cleavage site with a flexible ser/gly linker. However, the CMV pentamer as a subunit immunogenic composition was known in the art, as evidenced by the teachings of Carfi, Orlinger, Kabanova, Shenk, Cui, Spaete, and Mond (detailed supra.) The expression of CMV gH and gL, as the fusion protein provided for in the instant and ‘436 claims, would be obvious to use in combination with the UL128, UL130, and UL131A proteins, as these five proteins were known to formulate the CMV pentamer, which is important immunogenically and for viral attachment and entry, and inherently comprises oligomerization domains (Carfi ¶[0056].) Generation of fusion proteins of the pentameric proteins would be obvious given the teachings of Mond and Orlinger. The ‘436 claims provide that CMV gB may be in the composition, and it would be obvious to have it in the same composition as the PC as a multimer with the furin site replaced by a flexible linker, as evidenced by the teachings of Cui. One of skill in the art would be motivated to add gB to the composition, given the teachings of Carfi, Cui, Orlinger, and Kabanova. The linkers used for such a fusion protein would be obvious ser/gly linkers, and were well-known in the art, as evidenced by Mond and Cui. Mond teaches a fusion protein joining a first protein antigen, a linker, a second protein antigen, and an oligomerization domain, wherein the oligomerization domain may be a GCN4 yeast leucine zipper, T4 bacteriophage fibritin motif, or a eukaryotic GNC4 transcription factor motif (entire document; see reference claims 1, 21-25.) The sequences claimed, as well as the regions which would be removed, would be obvious to a skilled artisan, especially given the teachings of Carfi and Spaete. Therefore, the differences between the instant claims and the ‘436 claims would be obvious optimizations to make for a skilled artisan, as evidenced by the teachings of Carfi, Orlinger, Kabanova, Shenk, Cui, Spaete, and Mond.
(New rejection – necessitated by amendment.) Claims 94, 107, 109-110, and 118-120, and 122-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-6, and 8-15 of U.S. Patent No. 10,821,173 in view of Carfi, Carfi-460, and Kabanova (supra.) Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to compositions comprising viral proteins, wherein said viral proteins are expressed as multimers in fusion proteins along with other related viral proteins which also form multimers with themselves, other proteins, or the fusion protein itself. Both sets of claims are drawn to wherein the fusion protein is chosen from a combination of at least two viral antigens, including herpesvirus gH and gL. Both claim the proteins are joined by linkers. The main difference between the instant claims and the ‘173 claims is that the ‘173 claims are drawn to the antigens forming a multimerization complex in a cell with a heterologous multimerization domain, while the instant claims provide for the specific complex proteins from CMV, namely gH, gL, UL128, UL130, and UL131A, along with HCMV gB as a trimer with the furin site replaced by a flexible ser/gly linker. However, the CMV pentamer and CMB gB trimer as a subunit immunogenic composition was known or suggested in the art, as evidenced by the teachings of Carfi, Orlinger, Kabanova, Shenk, Cui, Spaete, and Mond (detailed supra.) The expression of CMV gH and gL, as the fusion protein provided for in the instant and ‘173 claims, would be obvious to use in combination with the UL128, UL130, and UL131A proteins, as these five proteins were known to formulate the CMV pentamer, which is important immunogenically and for viral attachment and entry. The specific constructs of CMV gH and gB would be obvious, given the teachings of Carfi, Shenk, Spaete, and Orlinger, and adding trimeric prefusion CMV gB to a composition comprising CMV PC would be obvious, given the combined teachings of Carfi, Cui, Orlinger, and Kabanova. The sequences of the proteins were provided in the art as evidenced by Carfi and Spaete, and the use of flexible ser/gly linkers to replace the furin cleavage site in CMV gB would be an obvious optimization given the teachings of Cui. Therefore, the differences between the instant claims and the ‘173 claims would be obvious to a skilled artisan, as evidenced by the teachings of Carfi, Orlinger, Kabanova, Shenk, Cui, Spaete, and Mond.
Response to Arguments
Applicant's arguments filed 10/22/2025 have been fully considered but they are not entirely persuasive. While the original rejections over the ‘844, ‘173, and ‘436 patents have been withdrawn in light of the amendments to the claims, new rejections over these patent claims is set forth and therefore arguments regarding these patents will be addressed as applicable herein.
Applicant argues that none of the cited claims of the patents recite the specific combination of CMV antigens as instantly claimed, and none of the teachings cited render obvious said antigens. While this was convincing with respect to the previous rejections, new NSDP rejections were made utilizing further pieces of art to show that even in light of the amendments to the claims, the instantly claimed compositions would still be obvious variants of the patented claims for the reasons set forth supra with each new rejection.
For the reasons set forth supra, the instant claims and the patented claims are still determined to be obvious variants of one another, and are not patentably distinct.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671