DETAILED ACTION
Disposition of Claims
Claims 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230381298A1, Published 11/30/2023.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Of note, there is not an attorney of record on file due to a lack of an official power of attorney of record. While a customer number has been provided on the ADS submitted 04/07/2023, this is not the equivalent of a power of attorney or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, it is suggested that a power of attorney be filed as per MPEP §402 or MPEP §1807, or an Authorization to Act in a Representative Capacity be filed as per MPEP §403 in order for the Office to freely and openly discuss the merits of the case with the applicant's representative(s). Please refer to https://www.uspto.gov/about-us/contact-us if you have questions regarding the proper filing of a power of attorney.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/11/2023 and 10/23/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claims 8, 26, 28, and 55 are objected to because of the following informalities: only one period can be present per claim (See MPEP § 608.01(m)). It is suggested that the claims be amended to have a colon or parentheses instead of a period after the lower case roman numerals (i.e. “ii)” instead of “ii.”). After the recitation of “SEQ ID NO”, a colon should be used instead of a period (i.e. “SEQ ID NO:” instead of “SEQ ID NO.”) Appropriate correction is required.
Claim 9 is objected to because of the following informalities: the definition of the abbreviation “EBV” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … Epstein-Barr virus (EBV)...).
Appropriate correction is required.
Claim 14 is objected to because of the following informalities: the definition of the abbreviations “α-GalCer” and “Pam3CSK4” are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … α-Galactosylceramide (α-GalCer)... and … Pam3CysSerLys4 (Pam3CSK4)…).
Appropriate correction is required.
Claim 44 is objected to because of the following informalities: the wording of the claim is awkward, creating potential ambiguity between what the method entails and the antecedent basis of all the limitations. One suggestion is to amend the claim along the lines of: “A method for generating a prophylactic or therapeutic formulation for treatment of herpesvirus infection, comprising: combining the composition of claim 26 with a pharmaceutically acceptable excipient to generate a formulation, wherein the formulation is suitable for administration to a subject in need thereof.”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 9 and 32 are 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.
Claim 9 is drawn to the pharmaceutical composition of claim 8, wherein the immunogenic glycoprotein is derived from EBV, and comprises at least one of glycoprotein 350 (gp350), glycoprotein B (gB), glycoprotein H (gH), glycoprotein L (gL), gHgL complex, glycoprotein 42 (gp42), any fragment thereof, or any combination thereof. Claim 32 is drawn to similar limitations, but depends upon the composition of claim 26.
First, the antecedent basis for “any fragment thereof” is unclear, as it is unclear if the “thereof” refers to each glycoprotein listed in the Markush group individually or only the gp42 complex (which immediately precedes it in the grouping). Further, mixing specific proteins (e.g. gH and gL) and making a complex and then claiming “fragments thereof” is unclear because it is unclear which fragments of each protein would be comprised within the scope of the claim, or if a complex would still be able to form. Stylistically, “gHgL” should also be “gH/gL” or “gH-gL” to ensure clarity as to the fact that there are two separate glycoproteins which comprise this complex, as the use of “gHgL” is unclear as to whether or not this is the name of the complex or if it is the proteins within said complex.
Second, the claim states that the glycoprotein is derived from EBV, yet it may comprise any of the glycoproteins listed in the Markush group, which are also found in other herpesviruses (e.g. gH is a conserved protein found in all herpesviruses, as is gL and gB.) It is unclear if this is meant to claim a fusion protein (e.g. a glycoprotein derived from EBV and an additional glycoprotein selected from those in the Markush group). It is therefore unclear if the Markush group is meant to further limit the “wherein the immunogenic glycoprotein is derived from EBV” or if the claim is meant to state that there is a glycoprotein derived from EBV and an additional glycoprotein from any other herpesvirus. Additionally, “derived from” can mean that said glycoprotein itself can be a mutant, variant, or chimera, and comprise material from a non-EBV source.
One suggestion to overcome these issues is to amend the claims along the lines of the following:
“Claim 9. The pharmaceutical composition of claim 8, wherein the immunogenic glycoprotein is derived from Epstein-Barr virus (EBV) and comprises at least one EBV glycoprotein selected from the group consisting of: glycoprotein 350 (gp350), glycoprotein B (gB), glycoprotein H (gH), glycoprotein L(gL), gHgL complex, glycoprotein 42 (gp42), fragments thereof, and combinations thereof.”
Claim 32 is rejected for similar reasoning.
For at least these reasons, claims 9 and 32 are rejected on the grounds of being indefinite.
Claim 14 and dependent claims 15 and 17 thereof are 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.
Claim 14 contains the trademark/trade names “MPL®”, “MONTANIDE™”, and “QUIL-A®”. Additionally, “lipovant” appears to be “LIPOVENT®”, which is also trademarked. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In reference to “MPL®”, the trademark/trade name is used to identify/describe monophosphoryl lipid A and, accordingly, the identification/description is indefinite. It is suggested that either only the full-length name be used (e.g. “monophosphoryl lipid A”) or that the abbreviation use the non-trademarked version often found in literature (e.g. “MPLA”).
In reference to “MONTANIDE™”, the trademark/trade name is used to identify/describe a brand of vaccine adjuvants manufactured by SEPPIC (Société d'Exploitation de Produits pour les Industries Chimiques) and, accordingly, the identification/description is indefinite. Further, as only “MONTANIDE™” is used and not the further descriptors (e.g. MONTANIDE™ ISA 51VG or MONTANIDE™ ISA 720VG), it is unclear what compositions are being claimed. MONTANIDE™ adjuvants are a range of oily adjuvants (Incomplete Freund Adjuvant) and it is unclear which adjuvant is to be encompassed by this limitation. LIPOVENT® is a trademark of Liposome Company, Inc. which covers pharmaceutical compositions comprising a specific type of liposomes.
In reference to “QUIL-A®”, the trademark/trade name is used to identify/describe a highly purified Quillaja saponaria Molina saponin product used in veterinary vaccines and, accordingly, the identification/description is indefinite.
Additionally, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 14 recites the broad recitation “a toll-like receptor (TLR) agonist”, and the claim also recites “monophosphoryl lipid A (MPLA)”, “lipid A”, “lipopolysaccharide”, “a cationic anti-microbial peptide (CAMP)”, “Pam3CSK4”, “trehalose dimycolate”, and “CpG DNA” which are narrower statements of the range/limitation. Additionally, “lipopolysaccharide” is a broad recitation that includes the more narrow “lipid A”, and “lipid A” is the broader recitation of lipopolysaccharides that include the narrower “monophosphoryl lipid A (MPLA)”. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
For at least these reasons, claim 14 is rejected on the grounds of being indefinite. Claims 15 and 17 are also included in this rejection as they depend upon claim 14, but fail to clarify the metes and bounds of claim 14.
Claim 15 and dependent claim 17 thereof are 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.
Claim 15 is drawn to the pharmaceutical composition of claim 14, wherein the adjuvant comprises a TLR9 agonist. However, from the wording of this claim, it is unclear if the adjuvant further comprises a TLR9 agonist along with one of the adjuvants listed already in claim 14, or if the claim is meant to further limit which adjuvant is to be chosen from claim 14, as CpG DNA (listed in claim 14) is a TLR9 agonist adjuvant. One suggestion is to have claim 15 depend directly upon claim 8, or to have claim 15 recite that it further comprises an additional adjuvant that is a TLR9 agonist. Due to the nature of dependent claim 16, the Office will use the former interpretation for the purpose of prior art rejections, but Applicant is free to amend the claims however they deem necessary in order to overcome this rejection.
For at least these reasons, the metes and bounds of claim 15 are unclear. Claim 17 is also included in this rejection as it depends upon claim 15, but fails to clarify the metes and bounds of claim 15.
Claim 19 is 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.
Claim 19 is drawn to the pharmaceutical composition of claim 8, comprising gp350, and further comprising a CpG ODN adjuvant. From the wording of the claim, it is unclear if these limitations are meant to exemplify the items listed in claim 8 as being within the pharmaceutical composition, or if these are additional items within the composition in addition to those listed in claim 8, items i-iii. The confusion especially arises from the use of “further comprising.” Additionally, the “comprising gp350” is unclear as it is unclear if the polyepitope of item i) comprises an epitope from gp350 or if the glycoprotein from item ii) comprises a gp350 sequence. For the purpose of prior art, claim 19 will be interpreted in the following manner:
“19. The pharmaceutical composition of claim 8, wherein the immunogenic glycoprotein of part ii) is EBV gp350, and wherein the adjuvant of part iii) is a CpG ODN adjuvant.”
For at least these reasons, claim 19 is rejected on the grounds of being indefinite.
Claim 25 is 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.
Claim 25 is drawn to a method for producing the polyepitope protein of claim 8, wherein said method includes steps for purifying the polyepitope protein under conditions that maintain the polyepitope protein in a substantially non-aggregated form. Claim 25 is attempting to claim a process without setting forth any steps involved in the process and is therefore indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). See MPEP §2173.05(q). While the word “steps” are recited in the claim, the “steps” that need to be performed are not clarified, and only the desired function/result is recited. Said method is recited at such a high, generic level that it is unclear how one of skill in the art is to actually perform said method.
Additionally, the term “substantially” in claim 25 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear if this is meant to indicate a certain percentage of non-aggregated particles or a certain Z-average score or polydispersity index (PDI).
For at least these reasons, claim 25 is rejected on the grounds of being indefinite.
Claims 26 and 55 and dependent claims 28, 32, 34, 44, 61, 63, 65, and 80-82 thereof are 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.
Claim 26 is drawn to a prophylactic or therapeutic composition for eliciting an immunogenic response in a subject against a herpesvirus, the composition comprising:
i) a polyepitope protein comprising amino acid sequences derived from two or more cytotoxic T-cell (CTL) epitopes, wherein the polyepitope protein comprises the amino acid sequences set forth in SEQ ID NOs: 1 and 11; or a nucleic acid encoding the polyepitope protein;
ii) at least one herpesvirus glycoprotein; or a nucleic acid encoding the at least one herpesvirus glycoprotein; and
iii) at least one adjuvant; or a nucleic acid encoding the at least one adjuvant. Claim 55 is drawn to a method for prophylactically or therapeutically treating a herpesvirus infection in a subject, comprising administration of the same claimed composition of claim 26.
With respect to the compositions claimed, there is a disconnect between the functional goal as recited in the preamble (“a prophylactic or therapeutic composition for eliciting an immunogenic response in a subject against a herpesvirus”, wherein “herpesvirus” reads broadly on any herpesvirus in the Herpesviridae family, which is over 100 different types of viruses), the structural limitation provided in part i) (“SEQ ID NOs: 1 and 11”, which are sequences from the Epstein-Barr virus (EBV) proteins EBNA1 and BZLF1, respectively, see Table 1 of specification), and the bridging language (“derived from two or more cytotoxic T-cell (CTL) epitopes” is broad and drawn to any potential CTL epitopes, not just herpesvirus-related epitopes, and the language regarding “derived from” also opens the limitation up to mutants and variants thereof of said epitopes.) From the claim construction, it is unclear whether the claimed composition is limited to EBV only due to the SEQ ID NOs used, or if the composition can be used against all herpesviruses, or if the use of any CTL from any source is critical somehow to the ability to use against all herpesviruses, not just EBV. As part ii) is drawn to the glycoprotein being from any herpesvirus, it is unclear if the limitations in part i) are for a specific purpose (e.g. to only treat EBV) or are acting in an adjuvanting fashion, thus supporting the activity of the adjuvant in part iii). Claim 28 provides for even more EBV epitopes (Table 1, different EBV CTL epitopes from different EBV proteins), causing more confusion as to the metes and bounds as to how the composition should effect the immunogenic response claimed. For at least these reasons, the metes and bounds of what is claimed and how it is to be accomplished is unclear in claims 26 and 55.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claims 26 and 55 are rejected on the grounds of being indefinite. Claims 28, 32, 34, 44, 61, 63, 65, and 80-82 are also rejected since they depend from claim 26 or claim 55, but do not remedy these deficiencies of claim 26 or 55.
Claim 63 is 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.
Claim 63 is drawn to the method of claim 55, wherein the glycoprotein is selected from gp350, gB, gH, gL, gHgL complex, gp42, any fragment thereof, or any combination thereof.
The antecedent basis for “any fragment thereof” is unclear, as it is unclear if the “thereof” refers to each glycoprotein listed in the Markush group individually or only the gp42 complex (which immediately precedes it in the grouping). Further, mixing specific proteins (e.g. gH and gL) and making a complex and then claiming “fragments thereof” is unclear because it is unclear which fragments of each protein would be comprised within the scope of the claim, or if a complex would still be able to form. Stylistically, “gHgL” should also be “gH/gL” or “gH-gL” to ensure clarity as to the fact that there are two separate glycoproteins which comprise this complex, as the use of “gHgL” is unclear as to whether or not this is the name of the complex or if it is the proteins within said complex.
One suggestion to overcome these issues is to amend the claims along the lines of the following:
“63. The method of claim 55, wherein the glycoprotein is selected from the group consisting of: gp350, gB, gH, gL, gHgL complex, gp42, fragments thereof, and combinations thereof.”
For at least these reasons, claim 63 is rejected on the grounds of being indefinite.
Claims 79 and 82 are 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.
Claim 82 is drawn to the composition of claim 81, wherein the nucleic acid sequence encodes one or more of the polyepitope protein, the at least one herpesvirus glycoprotein, and the at least one adjuvant. However, claim 81 is drawn to “ wherein the composition comprises one or more nucleic acid sequences encoding the polyepitope protein, the at least one herpesvirus glycoprotein, and the at least one adjuvant”. Claim 82 appears to be attempting to further limit claim 81 by going from multiple nucleic acid sequences (“one or more nucleic acid sequences” in claim 81) to one nucleic acid sequence (“the nucleic acid sequence” in claim 82), but it is unclear if the use of the definite article “the” refers back to only one nucleic acid sequence in the whole composition, or it is referring back to one of the “one or more nucleic acids” that are in the composition. Therefore, it is further unclear if each nucleic acid sequence encodes something, or only one specific nucleic acid sequence in claim 81 encodes something. It is suggested that claim 82 either be rewritten to narrow claim 26 to only reading on one nucleic acid sequence that encodes all three items, or that claim 82 be rewritten along the lines of “…wherein at least one of the one or more nucleic acid sequences encodes one or more of the polyepitope protein…”.
Claim 79 is rejected for similar reasoning.
For at least these reasons, claims 79 and 82 are rejected on the grounds of being indefinite.
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 8 is drawn to a pharmaceutical composition comprising:
i) a polyepitope protein comprising two or more amino acid sequences of cytotoxic T-cell (CTL) epitopes from herpesvirus antigens, wherein the polyepitope protein comprises proteasome liberation amino acids or amino acid sequences between at least two of said two or more CTL epitopes, wherein the polyepitope protein is capable of eliciting a CTL response upon administration to a subject as an exogenous protein; or a nucleic acid encoding the polyepitope protein;
ii) an immunogenic glycoprotein, or fragment thereof; or a nucleic acid encoding the immunogenic glycoprotein or fragment thereof; and
iii) an adjuvant; or a nucleic acid encoding the adjuvant.
Further limitations on the pharmaceutical composition of claim 8 are wherein the immunogenic glycoprotein is derived from EBV, and comprises at least one of glycoprotein 350 (gp350), glycoprotein B (gB), glycoprotein H (gH), glycoprotein L(gL), gHgL complex, glycoprotein 42 (gp42), any fragment thereof, or any combination thereof (claim 9); wherein the adjuvant comprises at least one of a toll-like receptor (TLR) agonist, a cationic anti-microbial peptide (CAMP), Adjuvant 65, α-Galactosylceramide (α-GalCer), aluminum phosphate, aluminum hydroxide, calcium phosphate, 3-Glucan Peptide, CpG DNA, GPI-0100, lipid A, monophosphorylated lipid A (MPLA), lipopolysaccharide, Lipovant, Montanide, N-acetyl-muramyl-L-alanyl-D-isoglutamine, Pam3CysSerLys4 (Pam3CSK4), quil A, or trehalose dimycolate (claim 14); wherein the adjuvant comprises a TLR9 agonist (claim 15), wherein the adjuvant is a CpG oligodeoxynucleotide (ODN), or an amphiphilic CpG ODN (claim 17); wherein the immunogenic glycoprotein of part ii) is EBV gp350, and wherein the adjuvant of part iii) is a CpG ODN adjuvant (claim 19); wherein the composition comprises the polyepitope protein, the immunogenic glycoprotein or fragment thereof, and the adjuvant (claim 77); and wherein the composition comprises one or more nucleic acid sequences encoding the polyepitope protein, the immunogenic glycoprotein or fragment thereof, and the adjuvant (claim 78), wherein at least one of the one or more nucleic acid sequences encodes one or more of the polyepitope protein, the immunogenic glycoprotein or fragment thereof, and the adjuvant (claim 79).
Claim 25 is drawn to a method for producing the polyepitope protein of claim 8,wherein said method includes steps for purifying the polyepitope protein under conditions that maintain the polyepitope protein in a substantially non-aggregated form.
Claim 26 is drawn to a prophylactic or therapeutic composition for eliciting an immunogenic response in a subject against a herpesvirus, the composition comprising:
i) a polyepitope protein comprising amino acid sequences derived from two or more cytotoxic T-cell (CTL) epitopes, wherein the polyepitope protein comprises the amino acid sequences set forth in SEQ ID NOs: 1 and 11; or a nucleic acid encoding the polyepitope protein;
ii) at least one herpesvirus glycoprotein; or a nucleic acid encoding the at least one herpesvirus glycoprotein; and
iii) at least one adjuvant; or a nucleic acid encoding the at least one adjuvant.
Further limitations on the composition of claim 26 are wherein the polyepitope protein comprises each of the CTL epitope amino acid sequences set forth in SEQ ID NOs: 1-20 (claim 28); wherein the glycoprotein is derived from EBV and comprises at least one of gp350, gB, gH, gL, gHgL complex, gp42, any fragment thereof, or any combination thereof (claim 32); wherein the adjuvant comprises a TLR agonist, and wherein the TLR agonist is a CpG ODN or a CpG ODN conjugated to a lipid (claim 34); wherein the composition comprises the polyepitope protein, the at least one herpesvirus glycoprotein, and the at least one adjuvant (claim 80); and wherein the composition comprises one or more nucleic acid sequences encoding the polyepitope protein, the at least one herpesvirus glycoprotein, and the at least one adjuvant (claim 81), wherein at least one of the one or more nucleic acid sequences encodes one or more of the polyepitope protein, the at least one herpesvirus glycoprotein, and the at least one adjuvant (claim 82).
Claim 44 is drawn to a method for generating a prophylactic or therapeutic formulation for treatment of herpesvirus infection, comprising: combining the composition of claim 26 with a pharmaceutically acceptable excipient to generate a formulation, wherein the formulation is suitable for administration to a subject in need thereof.
Claim 55 is drawn to a method for prophylactically or therapeutically treating a herpesvirus infection in a subject, comprising administering to the subject a composition comprising:
i) a polyepitope protein comprising amino acid sequences derived from two or more cytotoxic T-cell (CTL) epitopes, wherein the polyepitope protein comprises the amino acid sequences set forth in SEQ ID NOs: 1 and 11; or a nucleic acid encoding the polyepitope protein;
ii) at least one herpesvirus glycoprotein; or a nucleic acid encoding the herpesvirus glycoprotein; and
iii) an adjuvant; or a nucleic acid encoding the adjuvant.
Further limitations on the method of claim 55 are wherein the composition comprises 20-50 ug of the polyepitope protein (claim 61); wherein the glycoprotein is selected from the group consisting of: gp350, gB, gH, gL, gHgL complex, gp42, fragments thereof, and combinations thereof (claim 63); wherein the adjuvant comprises a TLR agonist, and wherein the TLR agonist is a CpG ODN or a CpG ODN conjugated to a lipid (claim 65)
Claim Rejections - 35 USC § 112(a); First Paragraph
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 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are rejected as lacking adequate descriptive support for generating any compositions or methods of use thereof, wherein said compositions comprise any polyepitope protein with any one or more cytotoxic T cell (CTL) epitopes from any herpesvirus antigens, any herpesvirus glycoprotein or fragment thereof, and any adjuvant, wherein said composition results in any of the claimed functions, such as generating CTL responses upon administration, or for use as a prophylactic or therapeutic composition for eliciting any immune response against any herpesvirus.
In support of the claimed genera (any herpesvirus, any CTL epitopes, any herpesvirus glycoprotein, any adjuvant), the application discloses one example in which an Epstein-Barr virus (EBV)-based polyepitope protein (EBVpoly) was generated and combined with the EBV glycoprotein gp350 and different human-compatible adjuvants (¶[0114]). EBVpoly is an artificial polyepitope protein consisting of 20 contiguous, minimal CD8+ T cell epitopes derived from eight EBV antigens (EBNA1, EBNA3A, EBNA3B, EBNA3C, LMP2A, BRLF1, BMLF1 and BZLF1)(¶[0115]). EBVpoly appears to have a nucleic acid sequence of SEQ ID NO: 42 (Table 3, ¶[0118]) and an amino acid sequence of SEQ ID NO: 21 (Table 3). The gp350 sequence used in the composition according to Table 3 was SEQ ID NO: 43 (amino acid) encoded by SEQ ID NO: 44 (nucleic acid). EBVpoly protein sequence was designed in such a way that the carboxyl terminus of each epitope was joined by a proteasome liberation amino acid sequence (AD or K or R). (See Table 1.) Proteasome liberation amino acid sequences improves the immunogenicity of CD8+ T cell epitopes by enhancing proteasomal processing of the polyepitope protein by the antigen presenting cells (¶[0118]). The EBVpoly protein was expressed from E. coli and isolated (¶[0119-0123]). The immunogenicity of the EBVpoly protein was evaluated first using peripheral blood mononuclear cells (PBMC) isolated from healthy, EBV-seropositive donors (Example 3 at ¶[0124]). EBVpoly protein was able to induce expansion of EBV-specific CD8+ T cells, restricted to multiple epitopes included in the EBVpoly protein, from all six donors. A large proportion of expanded cells demonstrated their functionality to degranulate (CD107a) and secrete multiple cytokines (INFγ, TNF and IL2)(¶[0127]; Fig. 2). In vivo murine animal studies for vaccine formulations comprising the EBVpoly protein were performed, wherein the vaccine formulations were prepared by mixing EBV gp350 (10 μg) and EBVpoly protein (40 μg), with amphiphile-CpG7909 (1.2 nmol) or soluble CpG7909 (1.2 nmol) per dose in 100 μl volume (Example 4 at ¶[0128]). The mice were vaccinated three times: priming dose on day 0; boosted on day 21 and 42 with an identical vaccine or control formulation (¶[0129]). The blood from these mice was analyzed for its ability to induce a CD8+ T cell response (Example 5 at ¶[0130]) and a CD4+ T cell response to gp350 (Example 6 at ¶[0134]). Both studies appeared to show the formulations with amphiphile-CpG7909 as the adjuvant generated superior responses (¶[0133][0137]), although the response appeared to have an HLA-restriction bias (Example 7 at ¶[0138]; Example 8 at ¶[0141]; Example 9 at ¶[0144]). The memory B cell response was assessed, with the two different vaccine groups producing comparable results with a slight increase in HLA A2 transgenic mice (Example 10 at ¶[0148]; Example 11 at ¶[0153]), and the neutralizing antibody and antibody isotype was assessed (Example 12 at ¶[0157] and Example 13 at ¶[0161]), again with the formulations with amphiphile-CpG7909 as the adjuvant generating superior neutralizing antibody responses. These experiments were also repeated with the adjuvant CpG1018 (Examples 14-20 starting at ¶[0165]), but it does not appear as though the results were compared to any other results aside those obtained with adjuvant-only controls.
All experiments were carried out with the EBVpoly protein of SEQ ID NO:21; no variants or mutants thereof were tested, nor were any other polyepitope proteins generated or tested that comprised any other CTL epitopes from any other sources (e.g. other non-EBV herpesviruses, other non-herpesviruses, etc.) No challenge experiments appear to have been performed using EBV or any other herpesvirus to show that the compositions were effective therapeutically and/or prophylactically. Only peptide vaccines were tested; no nucleic acid-based vaccines were generated or tested with any adjuvant. Only the adjuvants CpG1018, amphiphile-CpG7909, and soluble CpG7909 were tested with the EBV poly and gp350 composition. The only glycoprotein tested was EBV gp350; no other EBV glycoproteins or any other herpesvirus glycoproteins were tested. The claims recite compositions that can elicit any immune response against any herpesvirus, but the only specific structural limitations in the claims are directed towards the EBV epitopes (SEQ ID NOs: 1 and 11), wherein the other potential CTL epitopes may be from any source or sequence, the other herpesvirus glycoprotein may be from any source, and the adjuvant may be of any type/concentration. The specification does not demonstrate that such epitopes are effective against all herpesviruses generally. Therefore, the scope of the claimed compositions is not commensurate with the scope of what is described in the specification, and the application fails to provide sufficient examples of the breadth of species within the different claimed genera.
Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is no evidence that any polyepitope protein (or any nucleic acid encoding said polyepitope protein) comprising any CTLs, especially SEQ ID NOs: 1 and 11, can generate CTL immune responses in any host or provide therapeutic and/or prophylactic responses against any herpesvirus. Additionally, it is not clear that any herpesvirus glycoprotein can be within said polyepitope composition, as either a protein or nucleic acid encoding said glycoprotein, nor is it clear that said compositions are compatible with any adjuvant in any form to elicit the functional responses claimed.
The teachings of the art also fail to indicate that, without such evidence, those in the art would have expected the full scope of the claimed compositions and methods would confer the claimed functional results, namely therapeutic or prophylactic responses against any herpesvirus. In general, a search of the art indicates that modifications to biological molecules such as proteins are unpredictable, and require experimentation regarding the relationships between alterations in sequence bases/side chains and the function and structure of the protein in order to determine the actual effects of the modifications as discussed by Bowie et al. (Bowie JU, et. al. Science. 1990 Mar16;247(4948):1306-10; See page 1306). The art also shows that single amino acid mutations in the antibodies can greatly affect the ability of said antibody to bind to its target antigen (Winkler K, et. al. J Immunol. 2000 Oct 15;165(8):4505-14.; See also Kussie PH, et. al. J Immunol. 1994 Jan 1;152(1):146-52.) The art has further highlighted the importance of the order of CDRs, the interaction of non-CDR domains with respect to antigen/epitope binding, and that antigen-antibody algorithms or epitope prediction software/rational antibody design is highly inaccurate (Sela-Culang I, et. al. Front Immunol. 2013 Oct 8;4:302.) Computational in silico methods have traditionally struggled to predict the effect of mutations in antibody–antigen complexes on binding affinity, and generation of actual mutants in vitro of antibodies is the preferred and reliable method to determine the effect of mutations on antigen-antibody binding (Sirin S, et. al. Protein Sci. 2016 Feb;25(2):393-409. Epub 2015 Nov 6.) More specifically with respect to herpesviruses, while certain herpesvirus proteins may elicit cross-reactive responses, this cross-reactivity is mainly amongst members of the same sub-family (e.g. alpha, beta, or gamma herpesviruses)(Jing L, et. al. J Immunol. 2016 Mar 1;196(5):2205-2218. Epub 2016 Jan 25. ) Some cross-reactive responses amongst herpesviruses are detrimental to the host, as certain EBV or human herpesvirus type 6 (HHV-6) antigens can elicit immune responses that attack the host CNS (Almulla AF, et. al. bioRxiv 2025.04.02.646883; doi: https://doi.org/10.1101/2025.04.02.646883.) With respect to a CTL response, cross-reactivity is largely due to molecular mimicry and shared homology among viral proteins, such as: small subunit of ribonucleotide reductase (HSV UL40/VZV ORF18), viral enzymes and capsid proteins such as DNA polymerase, UL5, and UL12, and certain structural glycoproteins (gB is a major immunodominant target for cross-reactive CTLs.)(Balachandran N, et. al. J Virol. 1987 Apr;61(4):1125-35.) The art has noted that traditional methods of identifying CD4+ and CD8+ T cell epitopes which are conserved among HLA types with respect to any viral infection, especially herpesvirus infection, is critical, and that herpesvirus proteins traditionally recognized as generating neutralizing antibodies have shown to actually have poorer immune responses across HLA subtypes as compared to newer methods which identify less well-known epitopes that are highly conserved and immunogenic (Jing L, et. al. J Clin Invest. 2012 Feb;122(2):654-73. Epub 2012 Jan 3.) Even with this small incidence of cross-reactivity, a “universal” herpesvirus vaccine composition would not currently be feasible, as members of this family of viruses are highly sophisticated, co-evolved pathogens that establish lifelong, latent infections in nerve or immune cells, effectively hiding from the immune system. They use complex mechanisms to evade antibody detection, reactivate despite high immune responses, and have complex entry mechanisms that make it hard for a single vaccine to block infection (Cohen JI. J Clin Invest. 2024 May 1;134(9):e179483.) These data highlight the pitfalls in attempting to describe a product, such as a composition, functionally and broadly.
Thus, in view of the above, there would have been significant uncertainty as to which compositions comprising which polyepitope proteins, which herpesvirus proteins, and which adjuvants would be able confer the claimed functions of eliciting CTL responses, especially in eliciting immune responses against any herpesvirus that would have prophylactic and/or therapeutic benefit. In view of this uncertainty and the lack of sufficient examples of the claimed genera, the claims are rejected for lack of adequate written description support.
Claims 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compositions comprising a polyepitope protein comprised of EBV epitopes (EBVpoly protein of SEQ ID NO:21) in compositions comprising EBV gp350 protein and the adjuvant CpG1018 or CpG7909, and methods of eliciting an EBV-specific immune response with said composition, does not reasonably provide enablement for any compositions with any CTL polyepitope peptides, especially any CTL epitopes from any herpesvirus, and any herpesvirus glycoprotein, and any adjuvant, or compositions comprising nucleic acids encoding said components, and using said compositions (protein and/or nucleic acid compositions) to prophylactically or therapeutically inhibit any herpesvirus infection. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to compositions, especially prophylactic or therapeutic composition for eliciting an immunogenic response in a subject against a herpesvirus, wherein the composition is comprising:
i) a polyepitope protein comprising amino acid sequences derived from two or more cytotoxic T-cell (CTL) epitopes, especially wherein the polyepitope protein comprises the amino acid sequences set forth in SEQ ID NOs: 1 and 11; or a nucleic acid encoding the polyepitope protein;
ii) at least one herpesvirus glycoprotein; or a nucleic acid encoding the at least one herpesvirus glycoprotein; and
iii) at least one adjuvant; or a nucleic acid encoding the at least one adjuvant. The claims are also drawn to methods of making said polyepitope proteins and methods of using said compositions. The breadth of “herpesvirus” includes any member of the Herpesviridae family, which includes at least 100 known viruses. Further dependent claims focus on the proteins and sequences being derived from EBV. “Herpesvirus glycoprotein” would be any of the glycoproteins found in any of the herpesvirus envelope, such as gB, gH, gL, gD, gp350, or the like. “CTL epitopes” are cytotoxic T-Lymphocyte (CTL) epitopes, and are specific, short peptide fragments (typically 8-11 amino acids in length) derived from the processing of intracellular antigens (such as viral or tumor proteins) that are presented on the surface of cells bound to Major Histocompatibility Complex (MHC) class I molecules. They are recognized by the T-cell receptors (TCRs) of CD8+ T cells, resulting in the destruction of the presenting cell. “Adjuvant” is any substance added to a composition that enhances the immune response to said composition, and includes any type of immunostimulant (which directly activates the immune system) or delivery system (which provides a depot effect or transports an antigen to target cells) that aids in making the response to a composition, such as a vaccine composition, more effective. A “polyepitope” protein is any protein that comprises more than one epitope.
State of the prior art/Predictability of the art. The state of the prior art was briefly discussed supra with respect to the 35 USC 112(a) written description rejection and will be briefly expanded upon herein.
Herpesviruses are a family of over 100 viruses, which are further sub-divided into subfamilies based on biological properties, host range, and genome characteristics: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. Of the human herpesviruses that infect humans (of which there are 8, and are across all three subfamilies), only has one vaccine – that for the alphaherpesvirus varicella zoster virus (VZV). Human herpesvirus type 4 (HHV-4), a gammaherpesvirus known as Epstein-Barr virus (EBV), had no clinically-approved EBV vaccines at the time of filing, and no vaccines still post-filing, at part because the virus is complex, establishing life-long, mostly dormant latent infection in immune cells. EBV suffers from many of the same vaccine development issues as other herpesvirus family members, as Herpesviridae members establish lifelong infections in the host, hiding in immunoprivileged cells, and have large, complex genomes with multiple viral proteins that have immunoevasive mechanisms. Technical hurdles for EBV vaccines further include developing a vaccine that stops both B-cell and epithelial infections, lack of perfect animal models, and the long time between infection and EBV-related cancers.
Polyepitope peptides for herpesviruses are one approach for vaccine development, aiming to induce comprehensive immune responses, specifically both CD8+ cytotoxic T lymphocyte (CTL) and CD4+ T-helper responses, that are better than single-epitope vaccines. Polyepitope peptides are an advanced vaccine strategy for herpesviruses that involve linking multiple, minimal cytotoxic T lymphocyte (CTL) epitopes derived from various viral antigens into a single, contiguous “string-of-beads” construct. These constructs are designed to induce robust, broad-spectrum T-cell immunity, targeting different phases of the virus life cycle (lytic and latent) and accommodating diverse human leukocyte antigen (HLA) types. Polyepitope vaccines encoding T cell epitopes from various HCMV and EBV proteins were known in the art (Smith C, et. al. Hum Vaccin. 2010 Dec;6(12):1062-7. Epub 2010 Dec 1.) but were generated to be specific to a singular herpesvirus family member, and not to provide cross-reactive protection against more than one type of herpesvirus.
With respect to EBV, as noted in the art, the development of any successful CTL based approach to treat EBV associated diseases will need to target a broad range of CTL epitopes in order to cover the diversity of HLA types found in the human population. Polyepitope technology, which links CTL epitopes from a number of antigens across a range of HLA types contiguously, offers one potential strategy to target multiple antigens in a single construct. A synergistic approach combining a CTL based vaccine, such as an EBV-specific polyepitope, with a gp350-specific vaccine offers an attractive option for targeting humoral and cell mediated immunity (Smith, p. 1065). It remains, however, that the EBV vaccine art was and is highly unpredictable.
Working examples. The working example disclosed in the specification was described supra with the 35 USC 112 written description rejection. In summation, said examples utilized purified EBVpoly protein of SEQ ID NO:21 in compositions comprising EBV gp350 protein of SEQ ID NO:43 and the adjuvant CpG1018 or CpG7909. The compositions were delivered to HLA transgenic mice in prime/boost vaccination regimens and the immune response to said compositions analyzed. Note that due to the nature of EBV, which has limited host tropism, the mice were not challenged with EBV after the vaccinations, and instead the immune response to said vaccines were monitored through in vitro testing. Additionally, the mice were not challenged with any other herpesvirus to determine if said composition was sufficient to mount an immune response against any herpesvirus.
Guidance in the specification. The specification provides guidance towards compositions comprising the EBVpoly protein of SEQ ID NO:21, the EBV gp350 protein of SEQ ID NO: 43, and the adjuvant CpG1018 or CpG7909, and the delivery of said compositions to a subject. No challenge studies were performed with EBV or any other herpesvirus. No other polyepitope proteins were generated or tested. No other adjuvants were tested. No other EBV or non-EBV herpesvirus glycoproteins were tested. No nucleic acid vaccine compositions (DNA or RNA) were generated and tested.
Amount of experimentation necessary. Additional research is required in order to determine how effective the breath of the claimed polyepitope compositions would be in eliciting any type of CTL response, especially against any herpesvirus. Additional research is required to determine which combinations of polyepitopes, glycoproteins, adjuvants, and delivery system types (e.g. protein, nucleic acid, mixture, etc.) would be in methods of eliciting prophylactic and/or therapeutic immune responses against any herpesvirus.
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the breadth of the limitations within the claimed compositions and methods of making and using said compositions is sufficiently large that the potential permutations required for testing to show enabling support of the breadth of the claims is extremely large and undue.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make the claimed compositions and/or use the claimed methods.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 8, 14-15, 17, 25-26, 28, 34, 44, 55, 61, 63, 65, and 77-82 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khanna et. al. (US20150273051A1; Pub. 10/01/2015; hereafter “Khanna”.)
The Prior Art
Khanna teaches proteins which comprises CTL epitopes from two or more different herpesvirus antigens and further comprises an intervening amino acid or amino acid sequence between at least two of said CTL epitopes comprising proteasome liberation amino acids or amino acid sequences (entire document; see abstract.) Khanna teaches the isolated protein is capable of rapidly expanding human cytotoxic T lymphocytes (CTL) in vitro and eliciting a CTL immune response in vivo upon administration to an animal as an exogenous protein, wherein the isolated protein comprises no more than twenty (20) CTL epitopes derived from cytomegalovirus and/or Epstein-Barr virus antigens (entire document; see abstract.) Khanna teaches testing subunit vaccine formulations based on CMV-encoded glycoprotein B (gB) and polyepitope proteins tested in combination with human compatible TLR agonists (¶[0232]; instant claims 8, 14, 77). Khanna teaches
Khanna teaches the construction of an EBV polyepitope construct, which comprises proteasome linkers, called EBVpoly, and has a SEQ ID NO: 77, which comprises instant SEQIDNO:1 (HPVGEADYFEYR (EBNA1)) and instant SEQ ID NO:11 (LPEPLPQGQLTAYK (BZLF1)) at 100% identity, and EBVpoly (SEQ ID NO: 77) of Khanna comprises instant SEQ ID NOs: 1-20 at 100% identity (¶[0064]; Fig. 13; instant claims 26, 28, 80). Khanna teaches pharmaceutical compositions which comprise the polyepitopes, wherein said pharmaceutical compositions comprised pharmaceutically acceptable excipients (¶[0032-0035]; instant claim 44). Khanna teaches the pharmaceutical compositions may be used in prophylactic or therapeutic treatment of CMV and/or EBV infection (¶[0033]; instant claims 55, 63). Khanna teaches the polyepitope vaccine formulations were generated with 20 μg of polyepitope protein (¶[0226]; instant claim 61). Khanna teaches methods of expressing and purifying the EBVpoly peptide (¶[0247-0248]; instant claim 25). Khanna teaches the adjuvants may include TLR agonists, such as TLR4 or TLR9 agonists, including Monophosphoryl lipid A (MPLA) and/or immunostimulatory DNA such as CpG ODN1826, CpG ODN2006, CpG ODN2216 and/or CpG ODN2336 (¶[0037]; instant claims 14-15, 17, 34, 65). Khanna teaches that the vaccine compositions may be DNA vaccines, including DNA vectors, which encoded the proteins and elements discussed therein (¶[0162-0168][0183]; instant claims 78-79, 81-82).
Khanna therefore teaches the limitations of instant claims 8, 14-15, 17, 25-26, 28, 34, 44, 55, 61, 63, 65, and 77-82, and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 9, 19, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Khanna as applied to claims 8, 14-15, 17, 25-26, 28, 34, 44, 55, 61, 63, 65, and 77-82 above, and further in view of Smith et. al. (Smith C, et. al. Hum Vaccin. 2010 Dec;6(12):1062-7. Epub 2010 Dec 1.; hereafter “Smith”.)
The Prior Art
The teachings of Khanna have been set forth supra. While Khanna teaches the majority of the instant claims, and teaches that the composition may comprise a herpesvirus glycoprotein, Khanna fails to teach that said glycoprotein is an EBV glycoprotein, such as gp350. However, as Khanna teaches the combination of the polyepitope protein they developed along with the other known studied vaccine modality for CMV (e.g. gB subunit protein), it would be obvious to a skilled artisan to try a combination of the developed EBV polyepitope protein with any known EBV vaccine modalities, such as gp350, especially in light of the teachings of Smith.
Smith teaches that vaccination strategies that were used to treat EBV included EBV polyepitope CTL vaccines and recombinant gp350-based vaccines (Table 4). Smith teaches the development of any successful CTL based approach to treat EBV associated diseases will need to target a broad range of CTL epitopes in order to cover the diversity of HLA types found in the human population. Polyepitope technology, which links CTL epitopes from a number of antigens across a range of HLA types contiguously, offers one potential strategy to target multiple antigens in a single construct. A synergistic approach combining a CTL based vaccine, such as an EBV-specific polyepitope, with a gp350-specific vaccine offers an attractive option for targeting humoral and cell mediated immunity (p. 1065, left col., ¶1)
Given the related teachings of Khanna and Smith, one of skill in the art would be apprised as to the use of polyepitope vaccines for the treatment of EBV. Given the teachings of Khanna, one of skill in the art would be apprised as to the use of polyepitope peptides in combination with glycoprotein subunit compositions and adjuvants. It would be obvious to substitute one known element with another, especially given that it was known in the art to vaccinate individuals with the EBV glycoprotein gp350, and the specific combination of polyepitope vaccines with gp350-based vaccines was suggested by Smith. Therefore, arriving at the limitations of instant claims 9, 19, and 32 would be obvious to a skilled artisan, given the related teachings of Khanna and Smith.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Khanna in order to add EBV gp350 to the EBV polyepitope peptide compositions. One would have been motivated to do so, given the suggestion by Khanna that similar CMV polyepitope peptide vaccine compositions comprised known CMV glycoprotein subunit vaccines. There would have been a reasonable expectation of success, given the knowledge that the known vaccine modalities in the EBV art were gp350 subunit vaccines and CTL polyepitope vaccines, as taught by Smith, and given that Smith directly suggests combining the two modalities. 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-35 of copending Application No. 18/393,160 in view of Khanna and Smith (supra). NB: the teachings of Khanna are from the PGPub of parent Patent 9,901,632, but are available as prior art for the instant claims.
Both the instant claims and the ‘160 claims are drawn to peptide sequences which comprise a plurality of CTL epitopes from herpesvirus proteins, especially wherein said peptides utilize the proteasome liberation amino acid sequences. Both are drawn to wherein said CTL epitopes may be from EBV. Both sets of claims are drawn to nucleic acids encoding said peptides, and pharmaceutical compositions which comprise said proteins and additionally adjuvants. Both sets of claims are drawn to wherein the adjuvants may be TLR agonists, such as TLR4 or TLR9 agonists. Both sets of claims are drawn to methods of administering the compositions to a person to elicit a therapeutic or protective immune response. The main difference between the instant claims and those of the ‘160 claims is that the ‘160 claims provide for different CTL epitopes from the instant claims, and the ‘160 claims fail to specifically note the use of a herpesvirus glycoprotein in the composition. However, the differences in sequences and the use of glycoproteins would be obvious, given the teachings of Khanna and Ghost (both detailed supra.) Additionally, Khanna teaches the sequences of the ‘160 claims, and it would be an obvious modification to the instant claims to use the noted species identified by Khanna in the more broadly claimed instant claims. Therefore, the instant claims are an obvious variant of the ‘160 claims, especially in light of the teachings of Khanna and Smith, and are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Claims 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,896,665 in view of Khanna and Smith (supra). NB: the teachings of Khanna are from the PGPub of parent Patent 9,901,632, but are available as prior art for the instant claims.
Both the instant claims and the ‘665 claims are drawn to peptide sequences which comprise a plurality of CTL epitopes from herpesvirus proteins, especially wherein said peptides utilize the proteasome liberation amino acid sequences. Both are drawn to wherein said CTL epitopes may be from EBV. Both sets of claims are drawn to nucleic acids encoding said peptides, and pharmaceutical compositions which comprise said proteins and additionally adjuvants. Both sets of claims are drawn to wherein the adjuvants may be TLR agonists, such as TLR4 or TLR9 agonists. Both sets of claims are drawn to compositions for administering to a person to elicit a therapeutic or protective immune response. The main difference between the instant claims and those of the ‘665 claims is that the ‘665 claims provide for different CTL epitopes from the instant claims, and the ‘665 claims fail to specifically note the use of a herpesvirus glycoprotein in the composition. However, the differences in sequences and the use of glycoproteins would be obvious, given the teachings of Khanna and Ghost (both detailed supra.) Additionally, Khanna teaches the sequences of the ‘665 claims, and it would be an obvious modification to the instant claims to use the noted species identified by Khanna in the more broadly claimed instant claims. Therefore, the instant claims are an obvious variant of the ‘665 claims, especially in light of the teachings of Khanna and Smith, and are not patentably distinct.
Claims 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,065,329 in view of Khanna and Smith (supra). NB: the teachings of Khanna are from the PGPub of parent Patent 9,901,632, but are available as prior art for the instant claims.
Both the instant claims and the ‘329 claims are drawn to peptide sequences which comprise a plurality of CTL epitopes from herpesvirus proteins, especially wherein said peptides utilize the proteasome liberation amino acid sequences. Both are drawn to wherein said CTL epitopes may be from EBV. Both sets of claims are drawn to nucleic acids encoding said peptides, and pharmaceutical compositions which comprise said proteins and additionally adjuvants. Both sets of claims are drawn to wherein the adjuvants may be TLR agonists, such as TLR4 or TLR9 agonists. Both sets of claims are drawn to compositions for administering to a person to elicit a therapeutic or protective immune response. The main difference between the instant claims and those of the ‘329 claims is that the ‘329 claims provide for different CTL epitopes from the instant claims, and the ‘329 claims fail to specifically note the use of a herpesvirus glycoprotein in the composition. However, the differences in sequences and the use of glycoproteins would be obvious, given the teachings of Khanna and Ghost (both detailed supra.) Additionally, Khanna teaches the sequences of the ‘329 claims, and it would be an obvious modification to the instant claims to use the noted species identified by Khanna in the more broadly claimed instant claims. Therefore, the instant claims are an obvious variant of the ‘329 claims, especially in light of the teachings of Khanna and Smith, and are not patentably distinct.
Claims 8-9, 14-15, 17, 19, 25-26, 28, 32, 34, 44, 55, 61, 63, 65, and 77-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 9,901,632 in view of Khanna and Smith (supra). NB: the teachings of Khanna are from the PGPub of Patent ‘632, but are available as prior art for the instant claims.
Both the instant claims and the ‘632 claims are drawn to peptide sequences which comprise a plurality of CTL epitopes from herpesvirus proteins. Both are drawn to wherein said CTL epitopes may be from EBV. Both sets of claims are drawn to nucleic acids encoding said peptides, and pharmaceutical compositions which comprise said proteins and additionally adjuvants. Both sets of claims are drawn to wherein the adjuvants may be TLR agonists, such as TLR4 or TLR9 agonists. Both sets of claims are drawn to administering the compositions to a person to elicit a therapeutic or protective immune response. The main difference between the instant claims and those of the ‘632 claims is that the ‘632 claims provide for different CTL epitopes from the instant claims, and the ‘632 claims fail to specifically note the use of a herpesvirus glycoprotein in the composition. However, the differences in sequences and the use of glycoproteins would be obvious, given the teachings of Khanna and Ghost (both detailed supra.) Additionally, Khanna teaches the sequences of the ‘632 claims, and it would be an obvious modification to the instant claims to use the noted species identified by Khanna in the more broadly claimed instant claims. Therefore, the instant claims are an obvious variant of the ‘632 claims, especially in light of the teachings of Khanna and Smith, and are not patentably distinct.
Conclusion
No claims are allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN can be reached on 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights