DETAILED ACTION
Disposition of Claims
Claims 1-7, 9-11, 13-16, 20, 22, 24-25, and 33 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240100154A1, Published 03/28/2024.
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 07/28/2023, 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 09/20/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of implied phraseology (e.g. “Disclosed herein…” and “Disclosed are methods…” (multiple instance) and “Disclosed are glyco…”) and legal phraseology (e.g. the use of “e.g.” stands for “exempli gratia”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings are objected to because of the reference to color in the drawings (see e.g. ¶[0029][0031][0131]). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (See e.g. Fig. 2) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 1, 13, and 15 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 letter or number in the list (i.e. “a)” instead of “a.”). Appropriate correction is required.
Claim 1 is objected to because of the following informalities: because of the font usage, it is unclear that “ST6Gal1” is not “ST6Gall” or “ST6Ga11”. Looking to the guidance, it appears as though the protein claimed is “St6gal1” (¶0034]). It is suggested that either a different font be utilized for the claim set or this limitation be claimed in all capitalized letters so that it is clear what the acronym is in claim 1. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: the Markush group comprises both common names of virus families (e.g. “Herpesvirus”, “Poxvirus”, and “Hepadnavirus”) and also scientific names of virus families (e.g. “Asfarviridae”). It is requested that one format or the other be utilized throughout the claim set. Additionally, the family name of a virus is italicized. For the purpose of examination, the formal names of each viral family will be used “4. The method of claim 3, wherein the DNA virus is from the viral family selected from the group consisting of: Herpesviridae, Poxviridae, Hepadnaviridae, or Asfarviridae.”
Appropriate correction is required.
Claim 6 is objected to because of the following informalities: the definition of the abbreviation “HCV” 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. … hepatitis C virus (HCV)...).
Appropriate correction is required.
Claim 15 is objected to because of the following informalities: in the preamble, it should read “The method of claim 1, wherein…” and in part b) “representations” should be singular as only one representation of A2G2S2 is shown.
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.
Claim 1 and dependent claims 2-7, 9-11, 13-16, 22, and 24-25 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 1 is drawn to a method of producing a glyco-modified viral antigen comprising:
expressing a viral antigen in a recombinant mammalian cell line having:
a) one or more of the endogenous genes Mgat2, Mgat4A, Mgat4B, Mgat5, St3Gal3, St3Gal4, B4galtl, B4galt2, B4galt3, B4galt4, B4galt5, B3gnt2, St3Gal6, SPPL3, and/or FUT8 inactivated and/or downregulated; and
b) optionally a ST6Gal1 gene.
However, from the wording of the claim, it is unclear if the viral antigen comprises the ST6Gal1 gene (e.g. a viral antigen fusion to any ST6Gal1 gene of any origin). It would also be helpful if the claim is clarified to note that the “endogenous gene” that can be inactivated and/or downregulated is endogenous to said mammalian cell. While the specification notes the CHO cell line has been repaired to express ST6Gal1, it is not necessarily required that the gene be derived from said cell type/species.
Additionally, the use of only the acronyms creates uncertainty as to what genes/proteins are to be inactivated or downregulated. “Mgat2” is known in the art as both MGAT2 (N-acetylglucosaminyltransferase II), which is involved in glycosylation (glycan synthesis), and MGAT2 (Monoacylglycerol acyltransferase 2), which is involved in lipid metabolism (TAG synthesis).
Additionally, as the cell needs the functional protein generated in part b), and the protein products to either not be produced or those which are produced to be non-functional, it would be more proper to refer not to the gene, but the gene product/protein in the claim.
Further, the “endogenous genes” recited in claim 1 are not endogenous to all mammalian cells, or are differentially expressed in certain cells. For instance, MGAT2 is primarily found in small intestine, liver, stomach, kidney, and adipose tissue cells, and certain cell lines, like COS-7 cells, do not express “endogenous” MGAT2. ST3GAL6 has tissue-specific expression, namely the heart, placenta, and liver, and the expression of this protein is missing or lower in other cell types. The use of “endogenous” is confusing, as it insinuates the gene or protein is a natural part of said cell, when this is not always the case.
Finally, as part a) of the claim provides that the Markush group of genes which may be deleted is one or more, this makes it unclear how certain glycan products in dependent claims can be produced. For instance, FUT8 is important in fucosylation of proteins, yet if it is present in the cell line generating the viral antigen, it is unclear how a protein would lack fucosylation as in instant claim 15.
One suggestion to overcome some of these issues is to rewrite the claim along the lines of the following:
“1. A method of producing a glyco-modified viral antigen comprising:
expressing a viral antigen in a recombinant mammalian cell line, wherein said cell line comprises:
a) an inactivation and/or downregulation in one or more of the following proteins of said mammalian cell: alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (Mgat2), alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (Mgat4A) or B (Mgat4B), alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase (Mgat5), ST3 beta-galactoside alpha-2,3-sialyltransferase 3 (St3Gal3), 4 (St3Gal4), or 6 (St3Gal6), beta-1,4-galactosyltransferase 1 (B4galt1), 2 (B4galt2), 3 (B4galt3), 4 (B4galt4), or 5 (B4galt5), UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 2 (B3gnt2), Signal Peptide Peptidase-Like 3 (SPPL3), and/or fucosyltransferase 8 (FUT8); and
b) optionally, wherein said mammalian cell expresses a functional ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal1) protein.”
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claims 2-7, 9-11, 13-16, 22, and 24-25 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claim 3 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.
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 3 recites the broad recitation “RNA virus”, and the claim also recites “retrovirus” which is the narrower statement of the range/limitation. 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 claims.
Claim 5 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.
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 5 recites the broad recitation “Togavirus” (family of viruses or Togaviridae), and the claim also recites “Alphavirus” (genus of viruses) which is the narrower statement of the range/limitation. 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 claims. Additionally, it should be noted that some of the items recited in the Markush grouping are classes of viruses (e.g. Bunyaviricetes), some are families of viruses (e.g. Flaviviridae, Togaviridae, Orthomyxoviridae, Paramyxoviridae, Rhabdoviridae, Filoviridae), some are subfamilies of viruses (e.g. Coronavirus), and others are a genus of viruses (e.g. Deltavirus (Hepatitis D viruses), Alphavirus). It is highly suggested that in Markush groupings of viruses, that the grouping stick to one level of the International Committee on Taxonomy of Viruses (ICTV) classification system (e.g. the Markush group names only viral families.)
For at least these reasons, claim 5 is rejected on the grounds of being indefinite.
Claim 14 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 14 recites the limitation "the viral antigen" in line 2. The wording of the claim makes it unclear as to what the antigenicity is being compared to with the glyco-modified version of the viral antigen. It is unclear if the antigenicity is compared to the same unmodified viral antigen in a “wild-type” glycosylated state, or if said viral antigen was produced in a different cell line, etc.
Claim 15 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.
Regarding claim 15, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Therefore, the multiple recitations of “such as” in part a) of the claim render the metes and bounds of the claim unclear.
Claim 15 recites the limitation "the glycoproteins of interest" in lines 5-6. There is insufficient antecedent basis for this limitation in the claim. Additionally, the line “glycoproteins of interest produced being in with a fully sialylated bi-antennary structure without core fucosylation” is oddly worded, and it is unclear what is intended by this statement.
Additionally, in claim 15, the glycan structure of part c) is listed as:
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However, it is unclear if there are “gaps” in the structure to indicate optional sugars at these positions, or if the gaps were supposed to also comprise the same structure as that listed in part b), just showing the attachment sites of the sugars, but somehow the “NeuAc”, “Gal”, “GlcNAc”, and “Man” were not edited in correctly. As it is unclear what structure is being claimed in part c), claim 15 is rejected on the grounds of being indefinite.
Additionally, where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “mono-antennary, non-fucosylated (FA1G1S1)” in claim 15, namely the “F” before the remaining Oxford Notation of the glycan, are used by the claim to mean “a glycan which does not comprise a fucose,” while the accepted meaning of “F” when using Oxford notation is that said glycan comprises a fucose. See e.g. ¶[0064] with the error and Table 1, where the “F” is used contextually correctly. The term is indefinite because the specification does not clearly redefine the term. For the purpose of examination, it is unclear if the glycan structure of part (d) is meant to comprise or lack a fucose, so both formations will be examined.
For at least these reasons, claim 15 is rejected on the grounds of being indefinite.
Claim 20 and dependent claim 33 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 20 is rejected for not properly incorporating essential subject matter and information into the claim.
In the instant case, claim 20 refers to glycan structures in Table 1.
MPEP § 2173.05(s) discloses that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Further, the claim is indefinite because it is improper to import limitations from the specification into the claims, see MPEP §2111.01.
Since the exact Oxford notations of the glycan structures are known, as are brief descriptions of each glycan, it would be proper to import said elements into the claim.
Additionally, in claim 20, with respect to the limitation of “and further comprising one or more of the glycan structures of Table 1”, it is unclear which part of claim 20 is meant to comprise the glycan structures – if it is E1, E2, the first scaffold, the second scaffold, or a combination thereof.
For at least these reasons, claim 20 is rejected on the grounds of being indefinite. Claim 33 is rejected for depending upon claim 20, but not clarifying the metes and bounds of claim 20.
Claim 24 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 24 recites the limitation "a glyco-modified viral antigen" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Since the claim is referring back to a specific glycol-modified viral antigen, it should utilize the definite article “the” instead of the indefinite article “a”.
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 recites the limitation "a glyco-modified HCV E2 of claim 16" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 16 does not recite any specific HCV E2 antigen, and only generically references a glyco-modified viral antigen.
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 1 is drawn to a method of producing a glyco-modified viral antigen comprising:
expressing a viral antigen in a recombinant mammalian cell line, wherein said cell line comprises:
a) an inactivation and/or downregulation in one or more of the following proteins of said mammalian cell: alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (Mgat2), alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (Mgat4A) or B (Mgat4B), alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase (Mgat5), ST3 beta-galactoside alpha-2,3-sialyltransferase 3 (St3Gal3), 4 (St3Gal4), or 6 (St3Gal6), beta-1,4-galactosyltransferase 1 (B4galt1), 2 (B4galt2), 3 (B4galt3), 4 (B4galt4), or 5 (B4galt5), UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 2 (B3gnt2), Signal Peptide Peptidase-Like 3 (SPPL3), and/or fucosyltransferase 8 (FUT8); and
b) optionally, wherein said mammalian cell expresses a functional ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal1) protein
Further limitations on the method of claim 1 are wherein the viral antigen is a viral antigen from an enveloped virus (claim 2), wherein the enveloped virus is a DNA virus, RNA virus or a retrovirus (claim 3), wherein the DNA virus is from the viral family selected from the group consisting of: Herpesviridae, Poxviridae, Hepadnaviridae, or Asfarviridae (claim 4), wherein the RNA virus is a Flavivirus, Alphavirus, Togavirus, Coronavirus, Hepatitis D virus, Orthomyxovirus, Paramyxovirus, Rhabdovirus, Bunyavirus, or a Filovirus (claim 5); wherein the viral antigen is a hepatitis C virus (HCV) E2 glycoprotein (claim 6), wherein the HCV E2 glycoprotein is a modified HCV E2 glycoprotein (claim 7); wherein the viral antigen is a HCV E1E2 glycoprotein or a modified HCV E1E2 glycoprotein (claim 9), wherein the HCV E1E2 glycoprotein is a membrane bound HCV E1E2 glycoprotein (claim 10), wherein the membrane bound HCV E1E2 glycoprotein is a modified membrane bound HCV E1E2 glycoprotein (claim 11), wherein the modified HCV E1E2 glycoprotein comprises: a) a HCV E1 polypeptide, b) a first scaffold element, c) a HCV E2 polypeptide, and d) a second scaffold element, wherein the HCV E1 polypeptide does not comprise a transmembrane domain, and wherein the HCV E2 polypeptide does not comprise a transmembrane domain (claim 13); wherein the glyco-modified viral antigen has increased antigenicity compared to the viral antigen (claim 14); and wherein the glyco-modified viral antigen comprises one or more of the glycan structures:
a) a primary n-glycan structure that is a fully sialylated bi-antennary structure without core fucosylation, such as with more than 80%, such as 82%, such as 84%, such as 86%, such as 88%, such as 90% of the glycoproteins of interest produced being in with a fully sialylated bi-antennary structure without core fucosylation;
b) a glycan structure according to the structure A2G2S2 which is shown in the following picture:
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c) a glycan structure according to the structure:
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d) a glycan structure according to one or more of the structures: mono-antennary, no sialic acids (FA1G1); mono-antennary non-fucosylated, no sialic acids (A1G1); mono-antennary (FA1G1S1); or mono-antennary non-fucosylated (A1G1S1)(claim 15).
Claim 16 is drawn to a glyco-modified viral antigen produced by the method of claim 1.
Claim 20 is drawn to a glyco-modified hepatitis C virus (HCV) E1E2 glycoprotein comprising:
a HCV E1 polypeptide,
a first scaffold element,
a HCV E2 polypeptide, wherein the HCV E2 polypeptide does not comprise a transmembrane domain,
a second scaffold element, and further comprising one or more of the glycan structures of Table 1.
Further limitations on the method of claim 20 are wherein the HCV E1 polypeptide does not comprise a transmembrane domain (claim 33).
Claim 22 is drawn to a method of treating a subject in need thereof comprising: administering to the subject a composition comprising a therapeutically effective amount of one or more of the glyco-modified viral antigens of claim 16.
Claim 24 is drawn to a method of inducing an immune response in a subject in need thereof comprising: administering to the subject a composition comprising a glyco- modified viral antigen of claim 16.
Claim 25 is drawn to a method of treating a subject having HCV comprising administering to the subject a composition comprising a glyco-modified HCV E2 of claim 16.
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 1-7, 9-11, 13-16, 20, 22, 24-25, and 33 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 specific glycoengineered Chinese hamster ovary (CHO) cell lines which can generate differentially fucosylated HCV E2 ectodomain proteins, does not reasonably provide enablement for any glycoengineered mammalian cell line which can produce the specifically claimed glycans in the claimed abundance with improved immunogenicity with any viral antigen, and the use of any of said antigens produced in said systems for raising an immune response against said antigen, especially in a therapeutic or prophylactic setting, or for the generation of a glyco-modified HCV E1E2 construct. 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 a method of producing a glyco-modified viral antigen comprising:
expressing a viral antigen in a recombinant mammalian cell line having:
a) one or more of the endogenous genes Mgat2, Mgat4A, Mgat4B, Mgat5, St3Gal3, St3Gal4, B4galtl, B4galt2, B4galt3, B4galt4, B4galt5, B3gnt2, St3Gal6, SPPL3, and/or FUT8 inactivated and/or downregulated; and
b) optionally a ST6Gal1 gene. Further claims provide for viral antigens produced by said method, and the use of said viral antigen in methods of administering said viral antigen. The claims are also drawn to HCV E1E2 glycoprotein constructs, wherein the construct is glyco-modified. The term “glyco-modified” is defined at ¶[0045] to be a viral antigen that has a different glycosylation profile from how it would be generated in vivo. A “viral antigen” is any viral product (e.g. protein, nucleic acid, lipid, etc.) that would comprise any epitope and generate an immune response in a foreign host. The methods of treating a subject in need thereof is generating some sort of therapeutic effect in the subject towards any pathogen (instant claim 22; can be a homologous or heterologous pathogen in relation to the viral antigen of claim 1) or to HCV (instant claim 25; again, the viral antigen may be homologous or heterologous to the HCV.) The method of “inducing an immune response” is read as inducing any type of innate or adaptive immunity in said subject; it is not clear that said “immune response” is specific to the viral antigen being delivered, the glycans on said antigen, or both.
State of the prior art/Predictability of the art. Mammalian cell lines, primarily Chinese Hamster Ovary (CHO) cells, are the industry standard for producing complex therapeutic glycoproteins due to their ability to perform human-like glycosylation, such as N-linked glycosylation, which is crucial for protein stability, efficacy, and reduced immunogenicity. Key factors influencing glycosylation include the host cell's enzyme repertoire, intracellular sugar-nucleotide donor availability, and process conditions (media, temperature), with glycoengineering (knockouts/knock-ins) increasingly used to customize profiles (Butler M. Cytotechnology. 2006 Mar;50(1-3):57-76. Epub 2006 Jun 9.) While CHO cells are the workhorse of the biotechnology industry, and are valued for high-titer production and relatively safe, human-like glycan profiles. However, they can produce non-human epitopes like N-glycolylneuraminic acid (Neu5Gc) and Gal$\alpha$1,3-Gal (alpha-Gal), which may cause immunogenicity (Butler M, et. al. Curr Opin Biotechnol. 2014 Dec;30:107-12. Epub 2014 Jul 5.) HEK293 (human embryonic kidney cells), PER.C6 (human embryonic retinoblastoma cell line), and CAP (human amniocyte) cells provide more authentic human glycosylation, including complex sialylation, but historically had lower yields than CHO, although newer technology in glycoengineering has led to the production of human cells which can produce at much higher yields (Butler 2014, “Conclusions”.)
With respect to altering cell lines to generate a more universal glycosylation pattern, CHO cells were selected to isolate stable mutants. The ability to isolate glycosylation mutants in mammalian cells made it possible to unravel pathways of glycan synthesis and degradation and to identify, isolate, and map structural and regulatory genes. CHO cells became a focus for experiments to decipher glycosylation pathways and, importantly, provided mutant host cells for the production of viruses and glycoproteins with modified glycans. This proved to be extremely beneficial to the biotechnology industry because most recombinant therapeutics are glycoproteins.
However, while CHO and other mammalian cells can be altered to produce glycosylation mutants, all glycosylation genes and pathways have yet to be fully elucidated. Mutants in any cell type often accumulate the precursor immediately upstream of the block in a pathway and thereby reveal the structure of their substrate(s). Sequencing of mutant alleles reveals specific mutations that may give rise to a glycosylation phenotype. In most cases, mutations are loss-of-function and they reduce or abrogate the activity of an enzyme in a pathway; but there are also gain-of-function mutations that activate a silent glycosylation gene, elevate the expression of an existing activity, or inactivate a negative regulatory factor. In nearly all cases, glycosylation mutations lead to the presence of altered glycans on cell-surface glycoconjugates and changes in cell properties that link glycan structure to function. Although gene editing techniques using CRISPR/Cas9 or transcription activator-like effector nucleases (TALENs) are now the method of choice for introducing a mutation that weakens or ablates a glycosylation genes, initially such approaches did not allow for the serendipitous findings that often emerge from genetic screens. Subsequently, genetic screens were performed using HAP1 (haploid) human cells mutagenized by retroviral gene trap. Such unbiased screens led to the identification of multiple, previously unknown, glycosylation genes. Lately, however, the evolvement of CRISPR tools and the generation of genome-wide libraries have made it possible to conduct both loss-of-function and gain-of-function screens in nonhaploid cell lines, providing an unbiased strategy to discover new genes that influence cellular glycosylation.
Cells in culture mutate at a low rate (<10−6 mutations per locus per generation). In CHO cells, some loci are functionally haploid (single copy), and in HAP1 human cells, essentially all loci are haploid, which means that a single hit may generate a recessive mutant. However, typical mammalian cells are diploid and immortalized cells are often hyperploid, so the frequency of finding recessive mutants is low. Additionally, the identified endogenous genes in instant claim 1 are not present in all mammalian cell lines. For instance, MGAT2 is not found within COS-7 or STC-1 cell lines, as this is an endogenous protein mainly found in cells derived from the small intestine, liver, stomach, kidney, and adipose tissue.
To greatly increase the probability of finding desirable mutants, mutations may be induced by treating cells with chemical (e.g., alkylating agents), physical (e.g., ionizing radiation), or biological (e.g., a virus) mutagens or, perhaps more likely, by lentiviral transduction with CRIPSR/Cas9 genome-wide or focused libraries. Regardless of the method used to induce mutations, selection or enrichment is usually needed to find rare recessive or dominant mutants bearing a desired glycosylation phenotype. For example, direct selection for resistance to cytotoxic plant lectins that bind to cell-surface glycans gives a range of glycosylation mutants. Importantly, many mutants resistant to one or more lectins because of the loss of specific sugars become supersensitive to a different group of lectins that recognize sugar residues exposed by the mutation. The latter may be used to select for revertants in the original mutant population. Nontoxic lectins are also useful for enriching lectin-binding mutants (e.g., by flow cytometry). Mutations that affect all stages of glycosylation reactions, including the generation and transport of nucleotide sugars, have been identified using lectins as selective agents (Esko JD, et. al. Glycosylation Mutants of Cultured Mammalian Cells. In: Varki A, et al., editors. Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. Chapter 49. Available from: https://www.ncbi.nlm.nih.gov/books/NBK579983/ doi: 10.1101/glycobiology.4e.49.)
With respect to the glycosylation patterns on viral protein antigens, much research has been done to generate cell lines (e.g., EB66, CAP) to improve growth characteristics and glycosylation consistency. The need to optimize glycosylation patterns on viral antigens is necessary to increase the efficacy, safety, and stability of vaccines that utilize glycoprotein viral antigens. Proper glycosylation, particularly the presence of complex, human-like glycan structures, directly correlates with higher levels of neutralizing antibodies. However, viruses often use glycosylation to create a "glycan shield" to avoid detection, which is important to replicate in vaccine development for proper immune recognition but also important to investigate to determine if different glycosylation patterns allow for hidden epitopes to more readily be “seen” and neutralize the virus. Glycosylation dictates the proper folding and structural integrity of viral surface proteins, ensuring the vaccine mimics the real virus (Schwarzer J, et. al. Vaccine. 2009 Jul 9;27(32):4325-36. Epub 2009 May 14.)
With respect to hepatitis C virus (HCV), the art is very unpredictable as to how alteration of the glycosylation of HCV surface proteins E1 and E2, which form the entry complex for the virus, alters the antigenicity of the resulting HCV proteins. HCV E2 protein is heavily glycosylated, which masks conserved neutralizing epitopes and limits the immune response. While mammalian cells (HEK293) yield complex, human-like glycan structures, insect cells (Sf9/S2) produce paucimannosidic glycans. Some studies show insect-derived E2 (sE2) may be more immunogenic due to reduced shielding, while others find mammalian-derived E2 offers better conformational stability (Urbanowicz RA, et. al. J Virol. 2019 Mar 21;93(7):e01403-18.) Ren et. al. (Ren Y, et. al. Biochim Biophys Acta. 2016 Aug;1860(8):1764-75. Epub 2015 Aug 14.) teaches that mutation of the E1E2 N-linked glycosylation sites so that said sites were non-functional increased the immunogenicity of the resulting DNA plasmid vaccine, especially when used in conjunction with CpG adjuvant. However, another report (Slater-Handshy T, et. al. Virology. 2004 Feb 5;319(1):36-48.) shows that ablation of N-linked glycosylation sites when produced in Huh-7 or BHK-21 cells altered the ability of the protein to be transported through the secretory pathway, with noticeable reductions in the amounts of E2 secreted from cells. Multiple mutations altered the ability of the protein to properly fold and be excreted at all, and likely alters its ability to properly form the E1/E2 complex. Urbanowicz notes the discrepancies in the art in comparison to their findings and the findings of Li et al (Li D, et. al. J Virol. 2016 Nov 14;90(23):10486-10498.), as Urbanowicz showed comparable responses to sE2 produced in HEK293 vs Sf9 cells, while Li showed a superior immune response in the insect-cell produced antigen (p. 14 of Urbanowicz). This uncertainty is echoed by Pierce et. al. (Pierce BG, et. al. J Virol. 2020 Oct 27;94(22):e00704-20.), who notes they used insect cell expression to alter the N-glycan profile of sE2 versus that of mammalian cell-expressed sE2, and other investigators have recently tested immunogenicity for glycan-deleted E2 and E1E2 variants, but in neither case was a significant improvement in homologous and heterologous NAb responses observed for immunogens with altered glycans. Pierce notes these results suggest that glycoengineering of E2 or E1E2 represents a more challenging, and possibly less beneficial, avenue for HCV immunogen design; however, a report of success by other investigators through insect cell-expressed sE2 indicates that altered glycosylation may help in some instances. Therefore, with respect to HCV glycosylation of the E1 and/or E2 proteins, the art at the time of filing was very unpredictable.
Applicant-related post-filing art (Toth EA, et. al. Viruses. 2021 May 29;13(6):1027.) has also highlighted the continued issues with generation of HCV antigens for vaccines, noting that one bottleneck in the development of an E1E2-based vaccine is that the antigen is challenging to produce in large quantities and at high levels of purity and antigenic/functional integrity. Toth notes in developing a prophylactic vaccine for HCV, the HCV envelope glycoprotein complex, as the target of the protective antibody response, is currently the prime candidate. The envelope of HCV contains two glycoproteins, E1 and E2, that are encoded as part of the HCV polyprotein expressed in infected liver cells. This polyprotein is processed in the endoplasmic reticulum (ER) by signal peptidases and cellular glycosylation machinery to produce the mature E1E2 complex. These glycoproteins are membrane-anchored via their C-terminal transmembrane domains (TMDs), resulting in a membrane-bound E1E2 (mbE1E2) complex. A soluble version of the E2 protein (sE2) lacking the transmembrane domain has been the focus of a number of vaccine studies. However, immunological assessment in chimpanzees of an E1E2 vaccine produced superior immune responses compared to E2 administered alone and resulted in sterilizing immunity against a homologous virus challenge but with some cross-neutralization capacity against heterologous isolates. Moreover, E1E2 has been tested in humans and is well-tolerated. However, due to the limited neutralization breadth observed in the human clinical trial, ongoing research efforts are now focused on developing an optimized, modified form of E1E2 (mE1E2) that can elicit more robust, cross-neutralizing responses against multiple heterologous isolates. Toth further notes that the overall effect of mutations on potential glycan binding sites is unclear, as is whether the production of HCV antigens in different cell types has any effect on antigenicity. It is suggested that a system wherein the overall glycosylation pattern is homogeneous would be more useful to vaccine development. Further Applicant-related post-filing art (Kulakova L, et. al. NPJ Vaccines. 2025 Jun 11;10(1):121.) showed that these engineered CHO cells, which appeared to be those same CHO cells of the instant specification, while producing HCV antigens with more homogeneous glycosylation patterns, had unexpected functional effects on the antigen. For instance, one CHO cell line produced HCV antigen that was unable to bind to the native HCV entry receptor CD81. The Kulakova study shows that a comprehensive analysis of biochemical properties, serological data, and glycan profiles can yield information about which glycans to retain and which ones to avoid for a given antigen. Kulakova notes a more thorough, systematic analysis using all of the geCHO cell lines could reveal additional glycans that correlate with neutralization potency, along with epitope-specific effects of different glycans, perturbations to biochemical properties, and changes to antigen structure. Therefore, there is still significant uncertainty in the post-filing art with respect to such systems to develop HCV subunit antigens with altered glycosylation.
Working examples. The working example disclosed in the specification generated a panel of 8 CHO cell lines, wherein 7 appeared to produce sufficient protein for the experiments to generate HCV E2 (¶[0108]). The panel of CHO cells produced is provided for in Table 1 (¶[0109]). The isoforms #1 (ST3gal3/4/6, b3gnt2, sppl3 knockouts), #2 (ST3gal3/4/6, b3gnt2, sppl3, fut8, mgat2 knockouts), #4 (ST3gal3/4/6, b3gnt2, sppl3, fut8, mgat2 knockouts, St6gal1 knock-in), and #7 (ST3gal3/4/6, b3gnt2, sppl3, fut8, mgat4a/4b/5 knockouts, St6gal1 knock-in) produced glycoforms of the expressed E2 protein that appeared to have a profile similar to smaller and more simple linked N-glycans generated in the host liver. Comparison of the Kd to panel of naturally-generated HCV antibodies was more effective as shown in Table 2 for antibodies CBH-4D, AR3A, HC84.26, was slightly improved for #1 and #2 with the first HCV1 antibody but no change with the second HCV1 antibody, showed no change for antibodies CBH-4D, and HC84.26, and was worse for antibody AR3A(¶[0109]). Further in silico modeling was performed, whose results did not correlate with the in vitro data, suggesting that a combination of glycosylation patterns was likely relevant towards immunogenicity (¶[0112-0113]). Only the binding to sE2 (secreted E2 glycoprotein ectodomain) was studied, as the binding to E1 or E1/E2 produced in said cells was not performed. Additionally, it is often shown that E1/E2 is in the correct conformation by performing binding tests to its cognate receptor, CD81, but no receptor binding assays appear to have been performed. Fig. 1B provides two different constructs for the sE2 protein, but it is unclear as to the sequence of said protein or which construct was expressed in the CHO cell line experiments. No other cell lines aside from the glycoengineered CHO cells were generated. While the genes were said to be “knocked out” or “knocked in”, it is unclear how this was engineered in the cell line (e.g. if the entire open reading frames (ORFs) were deleted, how and where other genes were introduced into the CHO cells, how these genes could be “downregulated” aside from full deletion of the ORF, etc.) The glycoengineered HCV was not tested in vivo to determine the immunogenicity of said antigen in comparison to any other HCV E1, E2, or E1/E2 constructs. No other antigens from any other viruses or other pathogens were tested in this CHO system. The breadth of the claims covers homologous and heterologous vaccination regimens, yet no vaccination in any in vivo system against any viral antigen was performed to show any type of therapeutic benefit from the glyco-modified viral antigen generated in the system claimed.
Guidance in the specification. The specification provides guidance towards the generation of 8 CHO cell lines (Table 1), wherein said cell lines have specific sets of mutations that produce different glycosylation patterns on proteins produced in said cells. The specification provides guidance as to the expression of an unknown construct of HCV sE2 protein in 7 of these CHO cell lines.
Amount of experimentation necessary. Additional research is required in order to determine how effective the CHO cell lines would be in producing any viral antigen with any useful glycosylation pattern, especially for the use in compositions and methods for producing an immunizing immune response in any host as an “antigen”. It is unclear even with the sE2 produced in the glycoengineered cells if said sE2 would be useful in generating a therapeutic immune response, as post-filing art has even showed the uncertainty of similar systems and whether or not said HCV antigen was structurally similar to wild-type viral protein, as critical functionality was lost (e.g. ability to bind to cognate entry receptor) after expression in these CHO cells. No other mammalian cells (e.g. HEK293, MDCK, Vero, MRC-5, etc.) were glycoengineered and tested for their ability to produce any glyco-modulated viral antigen.
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 breath of the different genera (e.g. potential mammalian cell lines to be altered, the different gene mutations that can be made in said cells to alter the glycosylation patterns, the different viral antigens that could be produced in said system) coupled with the level of uncertainty in the art make the amount of experimentation that would be required to enable the breadth of the claims undue.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products and methods.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-7, 9-11, 13-16, 20, 22, 24-25, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Voldborg et. al. (WO2019105770A1, Pub. 06/06/2019; hereafter “Voldborg”) in view of Grzyb et. al. (Grzyb K, et. al. Sci Rep. 2016 Aug 2;6:30627.; hereafter “Grzyb”) and Cao et. al. (Cao L, et. al. PLoS Pathog. 2019 May 22;15(5):e1007759.; hereafter “Cao”.)
The Prior Art
Voldborg teaches methods to shift the glycosylation profile of recombinant produced serum glycoproteins to the predominant bi-antennary form found in human plasma by providing a mammalian cell line with a series of gene disruptions and/or gene insertions that facilitate this shift (entire document; see abstract.) Voldborg teaches a recombinant mammalian cell line having a) one or more of the endogenous genes Mgat4A, Mgat4B, Mgat5, St3Gal3, St3Gal4, St3Gal6, SPPL3, and FUT8 inactivated and/or downregulated; and b) optionally a gene ST6Gal1 inserted (reference claim 1), wherein the cell line is a CHO cell line (reference claim 8). Voldborg teaches that the cell line may express a glycoprotein of interest, such as a recombinant protein of interest (p. 8, ¶1). Voldborg teaches the cell line may generate glycan structures according to A2G2S2 (p. 21, instant claim 15).
While Voldborg teaches the cell line production system of the instant claims, Voldborg is silent as to producing viral antigens in said cell line, especially HCV E1E2 antigens which lack transmembrane domains yet are joined by linkers or scaffold proteins. However, using a cell line that generates a more human-like glycosylation pattern for viral antigens would be obvious to a skilled artisan, given the teachings of Grzyb, and such E1E2 constructs were known in the art, as evidenced by Cao.
Grzyb teaches generation of full-length (fE1E2) and soluble (tE1E2) HCV antigens in the cells of Leishmania tarentolae, wherein said cells have been glycoengineered to generate a more human-like glycosylation pattern in expressed proteins (entire document; see abstract; p. 2, ¶2). Grzyb teaches the fE1E2 comprised the entire wild-type sequence for said proteins with a tag to allow for easier purification from the membrane, while tE1E2 lacked ectodomains for both the E1 and E2 proteins (“Methods: Plasmid construction”, p. 8; instant claims 2-3, 5-7, 9-11). Grzyb teaches that vaccination with the generated E1E2 complexes are functionally relevant in that they bind to the cognate target cell receptor and that said proteins can be useful in vaccine platforms against HCV infection (p. 8, ¶2; p. 2, ¶6).
Cao teaches a modified HCV E1E2 glycoprotein complex with an Fc-tag (abstract, p. 2, ¶3) comprising a HCV E1 polypeptide lacking a transmembrane (TM) domain and a HCV E2 lacking a TM domain and the Fc fragments functionally act as “linkers” or “scaffolds” between the two protein ectodomains (Fig. 1; p. 5, “Expression of E1E2 heterodimer with a de novo designed heterodimeric tag”). Cao teaches this E1/E2 dimer can be used for prophylactic vaccines against HCV (p. 16, ¶1).
Given the teachings of Voldborg, one of skill in the art would be apprised as to mammalian cell lines which have been specifically engineered to generate more human-like glycosylation patterns on proteins. Given the teachings of Grzyb, one of skill in the art would be apprised as to the usefulness of cell systems that could generate human-like glycosylated viral proteins, especially for use in vaccines, as the glycosylation of HCV E1/E2 in this system appears to be more immunogenic than the glycosylation patterns produced in alternate cell systems. Given the teachings of Cao, one of skill in the art would be aware of soluble E1/E2 protein systems which could be readily expressed and isolated while retaining their immunogenicity and functionality. It would be obvious to determine if the glycosylation of the protein complex of Cao would be more immunogenic in an alternate cell expression system, such as that of Voldborg or Grzyb. Given that CHO cells are commonly used to generate vaccines and are approved expression systems for many regulatory authorities, it would be obvious to try the system of Voldborg for expression of the HCV antigens over that of Grzyb. Therefore, taken as a whole, the limitations of instant claims 1-3, 5-7, 9-11, 13-16, 20, 22, 24-25, and 33 would be obvious to a skilled artisan, given the combined teachings of Voldborg in view of Grzyb and Cao.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Voldborg in order to express other glycoproteins, thereby generating glycoproteins which would have a more human-related glycan pattern. One would have been motivated to do so, given the suggestion by Grzyb that the use of cells to propagate HCV E1/E2 antigens resulted in more immunogenic proteins if said cells utilized more human-like glycosylation patterns. There would have been a reasonable expectation of success, given the knowledge that soluble, native-conformation versions of HCV E1/E2 proteins were known in the art, as taught by Cao. 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 20 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18/252,800 in view of Grzyb and Voldborg (supra). Both are claiming HCV E1/E2 glycoproteins, wherein the E2 and E1 proteins lack a transmembrane domain, and wherein the E1 and E2 are linked by scaffold elements. The main difference between the instant claims and the ‘800 claims is that the instant E1/E2 construct has a modified glycan profile, namely a glycan of Table 1. However, such a difference would be obvious, given the teachings of Grzyb and Voldborg (detailed supra). Voldborg teaches the CHO cell lines which can generate proteins with modified glycans, such as A2G2S2 (see detailed analysis supra.) Grzyb teaches expression of HCV antigens in a cell line which generates a more human glycosylation pattern results in more immunogenic HCV E1/E2 antigens (see detailed analysis supra.)
Therefore, the differences between the instant claims and the ‘800 claims would be obvious modifications, and do not render the claims patentably distinct.
This is a provisional nonstatutory double patenting rejection.
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.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671