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 .
Election/Restrictions
The response to the Restriction/Election requirement filed 10 June 2026 is acknowledged. Applicant elects Group III, claims 43-45, directed towards a method of identifying an agent that interacts with one or more residues M84, F111, R117, F136, R212, R230, R234, R336, F342, A351, and N358 of the gO subunit of the gHgLgO trimer. Claims 1-7, 10, 13, 15, 25, 27-29, 31-32, and 34-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 June 2026.
Claim Status
Claims 1-7, 10, 13, 15, 25, 27-29, 31-32, and 34-45 are pending. Claims 1-7, 10, 13, 15, 25, 27-29, 31-32, and 34-42 are withdrawn as described above. Claims 43-45 are under examination in the instant office action.
Drawings
The Examiner notes that the instant Application contains colored drawings and that there is an approved petition for color drawings (2/15/2024) of record in the application.
Claim Objections
Claim 43 is objected to because applicant appears to have inadvertently recited “HMCV” rather than “HCMV” in parts (b) and (c) lines 5, 6, 7, 8, 9, 12, 13. The examiner requests that the first instance of the abbreviation be written out “human cytomegalovirus (HCMV)” and that the subsequent abbreviations be corrected to HCMV.
Claim Rejections - 35 USC § 112(a)
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.
Claims 43-45 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The following is an analysis of these factors in relationship to this application.
The breadth of the claims; nature of the invention
The instant claims are directed towards a method for identifying an agent that interacts with one or more residues M84, F111, R117, F136, R212, R230, R234, R336, F342, A351, and N358 of the gO subunit of the HCMV gHgLgO trimer, wherein the method comprises: a) providing an agent; b) contacting the agent with (i) a HCMV gHgLgO trimer comprising wild-type gO and (ii) an HCMV gHgLgO trimer comprising mutant gO under conditions permitting binding of the candidate agent with the HCMV gHgLgO trimer; and (c) measuring the binding of the candidate agent to (i) the HCMV gHgLgO trimer comprising wild-type gO and (ii) the HCMV gHgLgO trimer comprising mutant gO, respectively; wherein the mutant gO comprises the mutations M84R, F111R, R117E, F136R, R212E, R230E, R234E, R336E, F342E, A351 R, and N358R; and wherein a decrease in the binding of the candidate agent to the HCMV gHgLgO trimer comprising mutant gO relative to the HCMV gHgLgO trimer comprising a wild-type gO identifies the candidate agent as one that interacts with one or more of residues M84, F111, R117, F136, R212, R230, R234, R336, F342, A351, and N358 of the gO subunit of the HCMV gHgLgO trimer. The instant specification does not define “interact”; a person of ordinary skill in the art would understand that an agent that interacts with one of the recited residues to mean that the agent forms a non-covalent (e.g. hydrophobic or electrostatic) bond with that particular residue at the interfacial surface of the protein-protein interaction (See e.g. Moreira, Irina S., et. al. "Hot spots—A review of the protein–protein interface determinant amino‐acid residues." Proteins: Structure, Function, and Bioinformatics 68.4 (2007): 803-812). The claim is interpreted, therefore, to require the step wherein a decrease in the binding of the candidate agent to the HCMV identifies the candidate agent as one that forms a non-covalent bond with the particular residues recited.
The state of the prior art; level of one of ordinary skill; level of predictability in the art
As described above, the instant claims are directed at a method for identifying agents that interact with particular residues in the gO subunit of the gHgLgO trimer of human cytomegalovirus (HCMV). The art has previously identified the importance of particular sites in the gO subunit for formation of the gHgLgO complex (e.g., Stegmann, Cora, et al. "Importance of highly conserved peptide sites of human cytomegalovirus gO for formation of the gH/gL/gO complex." Journal of virology 91.1 (2017): 10-1128). Stegmann et. al. teaches that mutations in amino acids 181 to 186 or 193 to 198 resulted in the loss of the trimer and loss of viral growth (Abstract, Fig. 8), whereas other mutations in conserved areas resulted in partial loss of trimer formation. However, the particular binding sites of the gO subunit to PDGFRα are previously undescribed.
Regarding screening for agents that interact with, Wussow, Felix, et al. "Neutralization of human cytomegalovirus entry into fibroblasts and epithelial cells." Vaccines 5.4 (2017): 39 (Of record, IDS 12/20/2023) reviews the method of entry of HCMV into cell using the gHgLgO trimer (into fibroblasts) interaction with PDGFR-alpha. Wussow teaches “While our understanding of the glycoprotein complexes that are required for FB and EC infection has increased in recent years, the processes that mediate and neutralize initial attachment, receptor-binding, and membrane fusion during FB and EC infection remain poorly understood [30,38]” (p. 3, top ¶). Wussow et. al. also teaches “Similar assumptions [that Nab significantly contribute to both FB- and EC- specific Nab responses measured for HCMV seropositive individuals] may be made for NAb targeting gO or the gM/gN complex based on the potential involvement of these glycoproteins in HCMV entry and the neutralization capacity of isolated NAb targeting these glycoproteins” (p. 3 bottom ¶).
Some agents that bind to gO are known in the art; however, it is not clear what residues of gO that they interact with. For example, Gerna, Giuseppe, et al. "Monoclonal antibodies to different components of the human cytomegalovirus (HCMV) pentamer gH/gL/pUL128L and trimer gH/gL/gO as well as antibodies elicited during primary HCMV infection prevent epithelial cell syncytium formation” Journal of virology 90.14 (2016): 6216-6223 (Of record, IDS 12/20/2023) teaches the anti-gO antibodies CVB234 and CVB301 (Fig. 4, p. 6218 right column).
There are no teachings of record or in the art about the particular residues M84, F111, R117, F136, R212, R230, R234, R336, F342, A351, and N358 or about the mutated gO comprising M84R, F111R, R117E, F136R, R212E, R230E, R234E, R336E, F342E, A351R, and N358R.
Regarding charge mutants, the folding and interaction of proteins is highly unpredictable and a person of ordinary skill in the art (POSA) would not know, without additional experimentation, what the effects of the disclosed charge mutations in combination with each other would be on the folding and stability of the gO protein. For example regarding predicting the electrostatic interactions between charged proteins, Spector, Shari, et al. "Rational modification of protein stability by the mutation of charged surface residues." Biochemistry 39.5 (2000): 872-879 teaches “It is possible for there to be hydrophobic and van der Waals interactions between residues in the wild-type sequence or in any of the mutants in the cycle, and different reference states make it difficult to compare the results of different studies. Moreover, conformational changes between mutants complicate the analysis further. These additional interactions are not accounted for in studies in which only single mutations are made” (Introduction, ¶2) and “In this manner, all other interactions within the protein are kept constant, and only the electrostatic interactions formed by a single residue with each of the other charged and polar groups in the protein are considered. Even so, there are a large number of interactions to account for in the calculations. For such calculations to be tractable, it is helpful to choose smaller proteins as models” (Introduction, ¶3). Although Spencer et. al. was published in 2000, more recent work confirms the unpredictability of charge mutations on the folding and stability of a protein. For example, Tsai, Min‐Yeh, et al. "Electrostatics, structure prediction, and the energy landscapes for protein folding and binding." Protein Science 25.1 (2016): 255-269 teaches “The importance of such electrostatic guidance in folding dynamics, however, is unclear, since folding is mainly guided by water mediated interactions, both hydrophobic and hydrophilic.5, 6 Nevertheless, there is evidence that the folding funnel is sculpted by both electrostatics and shorter range forces. In the case of the ribosomal protein S6, for example, excess surface charges on the protein not only play the role of structural gatekeepers in protein-protein interactions, but also modulate protein stability and the choice of dominant folding route.7, 8” (Introduction, ¶1). Additionally, Tsai et. al. teaches “Sometimes long range electrostatic interactions not only provide charge−charge stabilization that funnels the landscape for binding but also help steer the docking of intrinsically disordered proteins before structure formation is completed. For other systems, on the other hand, long-range electrostatic interactions cause frustration in the landscape and would seem to impede protein dimer formation” (Introduction, ¶4).
The amount of direction provided by the inventor; existence of working examples; quantity of experimentation needed
The instant specification teaches a crystal structure of gO and interaction with PDGFRα (see e.g. Fig. 5C). The examples teach that gO at the N-terminus of the gH/gL/gO trimer interacts with PDGFRα via 4 interaction sites (Example 5, Fig. 5D; Table 3). Site 2 comprises residues R230, R234, V235, K237, and Y238 of gO; Site 3 comprises N81, L82, M84, M86, F109, F111, T114, Q115, R117, K121, and V123 of gO; Site 4 comprises R336, Y337, K344, D346, N348, E354, and N358 of gO (Example 5, Table 3). The addition of N-glycan introducing mutations alone did not significantly reduce binding of the trimer to PDGFRα, but the specification states that “a combination of N-glycan introducing mutations or the introduction of charge mutations at all four sites almost completely abolished the binding between PDGFRα and the trimer” (p. 35 lines 31-33). The instant specification teaches that a mutant comprising all of the mutations M84R, F111R, R117E, F136R, R212E, R230E, R234E, R336E, F342E, A351R, and N358R abolishes binding to PDGFRα (Fig. 7D). There is no teaching about how the mutations change the folding, stability, or structure of gO other than the prophetic recitation that it is a “charge mutant” and the showing that the binding to PDGFRα is abolished. It is unclear what affect those particular residue changes would have on the overall structure of the protein and its interaction with either PDGFRα or an unknown agent. Therefore, a person of ordinary skill in the art would not be able to recognize “wherein a decrease in the binding of the candidate agent to the HMCV [sic] gHgLgO trimer comprising mutant gO relative to the HMCV [sic] gHgLgO trimer comprising a wildtype identifies a candidate agent as one that interacts with one or more of the residues” because a POSA would not know whether the loss of binding reflected an interaction with one or more of those residues, or rather with a surface of the protein or with an adjacent residue that was changed by the introduction of those mutations into gO.
Conclusion
Applicant is not enabled for the instantly claimed method for identifying an agent that interacts with the recited residues, wherein a decrease in the binding of the candidate agent to the HCMV trimer comprising the mutant gO relative to the trimer comprising wildtype gO identifies the candidate agent as interacting with the recited residues because a POSA would not know from the art and the instant specification whether the agent interacts with the specifically recited residues by performing the method as claimed. It would take an undue amount of experimentation to practice the method because a POSA would require additional experiments, perhaps even solving a crystal structure complex, to determine whether the candidate agent was interacting with the particular recited residues or with adjacent residues or surfaces disrupted by the introduction of the charge mutations.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 43-45 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 43 and 44 are indefinite for the recitation of the positions M84, F111, R117, F136, R212, R230, R234, R336, F342, A351, and N358 in the gO subunit of HCMV without the backbone or numbering scheme of the gO subunit of HCMV defined. Regarding the gO subunit of HCMV, the specification recites “The terms "gO subunit of human cytomegalovirus (HCMV)", "gO subunit," and "gO," as used herein, broadly refer to any native gO from any mammalian source, including primates (e.g. humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses full-length gO and isolated regions or domains of gO. The term also encompasses naturally occurring variants of gO, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human gO is provided as SEQ ID NO: 1. Minor sequence variations, especially conservative amino acid substitutions of go that do not affect gO function and/or activity, are also contemplated by the invention” (p. 12 lines 9-15). However, the naturally occurring human CMV includes variants that have different sequence lengths than the instant exemplary gO sequence, such that, for example, M is not always position 84. Paradowska, Edyta, et al. "Distribution of the CMV glycoprotein gH/gL/gO and gH/gL/pUL128/pUL130/pUL131A complex variants and associated clinical manifestations in infants infected congenitally or postnatally." Scientific reports 9.1 (2019): 16352 teaches several variants of HCMV and uses an entirely different numbering system than the instant sequence—for example the strain AD169 in Fig. 2C shows that the residue labeled “84” is a tyrosine, and it appears that the residue in that sequence equivalent to M84 in the instant exemplary gO of SEQ ID NO: 1 is residue 97 of AD169 according to Paradowska. As such, a person of ordinary skill in the art would not understand what particular residues are encompassed by the metes and bounds of the claims.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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