DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Disposition of Claims
Claims 1, 4-5, 7, 9, 13, 15, 18-20, 36, 38, 41, 46-48, 50, 52-53, and 57 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2023/0341397 A1, Published 26 October 2023. Applicant’s amended Specifications as presented on 14 July 2023 and 10 March 2023 are acknowledged and entered.
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.
Information Disclosure Statement
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.
The information disclosure statement (IDS) submitted on 10 March 2023 has been considered, as a whole, by the examiner. Any individual references with strikethroughs, however, have not been considered.
Drawings
The Drawings are objected for containing references to colors. Specifically, Figures 8, 10, and 14 contain references to colors (i.e., red, green) either in the figures themselves or in the figure legends. Additionally, Paragraphs 0146, 0153, and 0157, at least, also refer to colors in the 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 objection to the drawings will not be held in abeyance.
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.
Specification
The abstract of the disclosure is objected to because the abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). 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).
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 4, 7, and 13 are objected to because of the following informalities: In Claim 4, it is suggested that it the word “virus” be removed from the phrase “SARS-CoV-2 virus genome” as use of the word “virus” is redundant in this context.
In Claim 7, it is suggested that it say “cleaved by a 3C-like protease” instead of “cleaved by 3C-like protease”.
In Claim 13, it is suggested that it say “cleaved by a papain-like protease” instead of “cleaved by papain-like protease”.
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 4 and 5 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.
Regarding Claim 4, it recites the limitation “wherein the 5’ untranslated region comprises a 5’ untranslated region of the SARS-CoV-2 virus genome”. Claim 4 recites the limitation "the SARS-CoV-2 virus genome" in Line 2. There is insufficient antecedent basis for this limitation in the claim, as Claim 1, upon which Claim 2 depends, does not introduce the limitation of “a SARS-CoV-2 virus genome”. The use of “the” in “the SARS-CoV-2 virus genome” also gives the impression that only one such genome exists. It is suggested that the claim be amended by replacing “the” with “a”, but Applicant is free to amend the claim as they deem necessary.
Additionally, the use of the phrase “a 5’ untranslated region” renders the claim indefinite because it is unclear how the claim should be interpreted due to the use of the indefinite article “a”. One interpretation is that the phrase refers to any part or region of a 5’ untranslated region, including a fragment of said 5’ UTR. Another interpretation is that it refers to the entire 5’ untranslated region found in a viral genome. This lack of clarity renders the claim indefinite. See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite."). It is suggested that the claim be amended by replacing “a” with “the” so that the claim now recites the limitation “wherein the 5’ untranslated region comprises the 5’ untranslated region of a SARS-CoV-2 virus genome”, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 4 is rejected on the grounds of being indefinite.
Regarding Claim 5, it recites the limitation “wherein the degron comprises a ubiquitin domain”. The use of the phrase “a ubiquitin domain” renders the claim indefinite because it is unclear how the claim should be interpreted as there is no specific definition provided in the instant Specification. One interpretation is that the phrase is referring to the entire ubiquitin molecule. Another interpretation is that it is only referring to a partial region or fragment of the ubiquitin molecule. This lack of clarity renders the claim indefinite. See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite."). It is suggested that the claim be amended such that it recites the limitation “wherein the degron comprises ubiquitin, optionally wherein the ubiquitin comprises the amino acid sequence of SEQ ID NO: 4”, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 5 is rejected on the grounds of being indefinite.
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, 4-5, 7, 9, 13, 15, 18-20, 36, 38, 41, 46-48, 50, 52-53, and 57 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 an isolated vector or isolated cell comprising said vector, does not reasonably provide enablement for a cell within a transgenic animal or a transgene therein. 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. Applicant broadly claims a cell, vector, or nucleic acid containing the nucleic acids of claims 1, 4-5, 7, 9, 18-19, 36, 38, and/or 46. The claims read on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the cell or vector.
State of the prior art/Predictability of the art. With respect to the unisolated cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et al., Current Opinion in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, are not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitations, "cell" and “vector” and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional polynucleotides that produce the claimed vector and variants thereof, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed vector is functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Working examples. No working example of a transgenic animal is disclosed in the specification. The only mention of a transgenic animal is in Paragraph 0130, which states that “polynucleotide sequences of the invention can be incorporated for introduction in transgenes for introduction into the genome of a transgenic animal”. The working examples disclosed in the Specification describe the cells and viral vector used to express the biosensor construct, such as HEK 293 cells and the BacMam vector delivery system (see Paragraphs 0137-0147).
Guidance in the specification. The specification provides guidance towards viral vectors as a potential delivery system for the claimed biosensors (see Paragraphs 0122-0128). The specification also provides guidance towards the polypeptides of the invention being expressed in bacterial cells, plant cells, yeast cells, or mammalian cells such as HEK 293 cells (see Paragraphs 0129-0132).
Amount of experimentation necessary. Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the biosensor encoded by the claimed vector.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, are not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claims to recite the term "isolated" before the recitations "cell" and “vector” and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using “purified” in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional polynucleotides that produce the claimed biosensor, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed biosensors are functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Claims 9 and 18-19 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 amino acid sequences which are 100% identical to instant SEQ ID NOs: 4, 6, and 13-14 and for amino acid sequences encoded by nucleotides sequences which are 100% identical to instant SEQ ID NOs: 7-9 and 23-24, does not reasonably provide enablement for variants of the claimed sequences with less than 100% sequence identity. 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 degron comprising an amino acid sequence that as 0-5 amino acid changes compared to the amino acid sequence of SEQ ID NO: 4, a cleavage site comprising an amino acid sequence that has 0-5 amino acid changes compared to the amino acid sequence of SEQ ID NO: 6, and a reporter protein comprising an amino acid sequence that is at least 75% identical to instant SEQ ID NO: 13 or 14.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e., inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Working examples. No working examples of the claimed variants are disclosed in the specification.
Guidance in the specification. The specification provides guidance towards constructs shown which are presumably 100% identical to the claimed sequences. The instant Specification, however, fails to disclose the critical or essential amino acids or nucleotides which must be present and any variants of the claimed sequences. Regarding the degron and cleavage site variants claimed in instant Claim 18, the instant Specification fails to disclose the critical or essential amino acids which must be present and that therefore cannot be changed. The instant Specification does not even provide insight into what kinds of mutations or changes can be tolerated.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide variants of known sequences will function as intended, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
Claims 9, 18, and 19 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 instant application attempts to tie function to sequence identity in the context of a vector comprising a nucleic acid comprising: a nucleotide sequence comprising a 5' untranslated region, a nucleotide sequence encoding a degron, a nucleotide sequence encoding a cleavage site, and a nucleotide sequence encoding a reporter protein, wherein the vector comprises a nucleotide sequence that is at least 75% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 7-9, 23 and 24, wherein the nucleotide sequence comprising the 5' untranslated region comprises a nucleotide sequence that is at least 75% identical to nucleotides 1,613-1,877 of SEQ ID NO: 11, wherein the degron comprises an amino acid sequence that has 0, 1, 2, 3, 4 or 5 amino acid changes compared to the amino acid sequence of SEQ ID NO: 4, and wherein the cleavage site comprises an amino acid sequence that has 0, 1, 2, 3, 4 or 5 amino acid changes compared to the amino acid sequence of SEQ ID NO: 6, wherein the reporter protein comprises an amino acid sequence that is at least 75% identical to SEQ ID NO: 13 or 14. While a percent identity threshold is provided in the claims for the claimed sequences, the instant Specification fails to disclose the critical or essential amino acids or nucleotides which must be present and that therefore cannot be changed. Regarding the degron and cleavage site variants claimed in instant Claim 18, the instant Specification fails to disclose the critical or essential amino acids which must be present and that therefore cannot be changed and no percent identity threshold is provided in the claims. The claim language does not limit how the claimed changes can be interpreted for either the degron or the cleavage site. Too many changes or even one severe change can alter the function of the degron and can inactivate the cleavage site or even change its specificity altogether. In particular, the cleavage site sequence, SEQ ID NO: 6, is only 10 amino acids long. This means that the claim language encompasses variants having as little as 50% sequence identity to SEQ ID NO: 6. The instant Specification does not even provide insight into what kinds of mutations or changes can be tolerated. As such, the claims read on variants of the claimed sequences with insertions, deletions, and even non-conservative substitutions present. As such, it would be unclear to a person having ordinary skill in the art to know what to change and what not to change.
Furthermore, while it is not explicitly stated, it is assumed that the constructs shown in the data provided have sequences which are 100% identical to the claimed sequences. Even if that is not the case, the data shown do not explicitly include any claimed variants having as little as 75% sequence identity, or even 76-99% sequence identity, in the case of Claim 19, raising questions about how effective these claimed variants would be in the experiments performed. Thus, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genera being claimed by Applicant have not been identified or disclosed. One way to obviate the instant Written Description rejection is for Applicant to show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claims 9, 18, and 19 do not meet the written description requirement.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 48 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). In Paragraph 0132 of the instant Specification, human cells are specifically contemplated. It is suggested that the claim be amended to recite “An isolated cell”, but Applicant is free to amend the claim as they deem necessary.
Claim Rejections - 35 USC § 103
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.
Claims 1, 5, 9, 15, 19-20, 36, 38, 41, 47-48, 50, 53, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. (US 2005/0214890 A1, Published 29 September 2005), Minshull and Theodorou (US 2015/0225468 A1, Published 13 August 2015), Ast et al. (US 2017/0247769 A1, Published 31 August 2017), Lakshmanan et al. (US 2021/0060185 A1, earliest Priority Date 28 August 2019), Brandon and Thomas (US 2008/0274988 A1, Published 06 November 2008), Bancel et al. (US 2014/0010861 A1, Published 09 January 2014), and Shaner et al. (U.S. Patent No. 10,221,221 B2, Issued 05 March 2019)
Tan et al. teach a protease activity assay system for determining the cleavage of more than one recognition or cleavage site in a single assay, wherein the assay system utilizes a fluorescent fusion substrate comprising a first fluorescent protein, a specific protease recognition site, and a second fluorescent protein (see Abstract), wherein the first fluorescent protein can be RFP and wherein the second fluorescent protein can be GFP (see Paragraph 0012). Tan et al. also teach an expression vector comprising a nucleic acid comprising the fluorescent fusion substrate construct (see Paragraph 0019; Figure 1) as well as a host cell comprising said expression vector (see Paragraph 0031). Additionally, Tan et al. teach a method for the screening of candidate protease inhibitors specific for a target protease (see Paragraphs 0073, 0077-0080, 0104, 0122, 0135), as well as a method for measuring virus propagation in cells (see Paragraph 0053, 0073, 0093, 0131), and measuring a signal from the reporter proteins (see Paragraphs 0008, 0012, 0016, 0048, 0104, 0115-0116).
Minshull and Theodorou teach an expression vector comprising a nucleic acid comprising a first nucleic acid sequencing encoding a fluorescent protein or polypeptide connected via a linker to a second polypeptide, wherein said linker encodes a 2A peptide (see Paragraphs 0024-0025) and wherein said 2A peptide has the sequence of any one of SEQ ID NOs: 101, 116, and 481, each of which is 100% identical to instant SEQ ID NO: 15 (see Sequence Listing; Paragraph 0030). Minshull and Theodorou also teach a host cell comprising said expression vector (see Paragraphs 0022-0023) and a biosensor encoded by said expression vector (see Paragraphs 0127, 0129, 0132, 0140, 0152), wherein said biosensor can be used as an indicator for protease activity or proteasome inhibition and wherein said fluorescent protein can be fused with a proteasome degradation signal (see Paragraphs 0131, 0134, 0153).
Ast et al. teach a vector containing a nucleic acid sequence encoding a fluorescent polypeptide which can be used as a fluorescent sensor, wherein said fluorescent polypeptide comprises a first fluorescent protein and a second fluorescent protein, and a cell comprising said vector, wherein said vector can be a baculovirus-derived vector and wherein said first fluorescent protein can be mCherry and wherein said second fluorescent protein can be mNeonGreen (see Abstract; Paragraphs 0079, 0081, 0101-0104, 0136; Table 1).
Lakshmanan et al. teach a biosensor of protease and/or protease-associated event (see Paragraph 0183), wherein said biosensor comprises a degron (see Paragraphs 0209-0212) and a 5’ untranslated region (see Paragraphs 0256-0258, 0262), as well as a method for detecting protease activity in a cell by measuring a signal from the biosensor (see Paragraphs 0152-0153).
Brandon and Thomas teach SEQ ID NO: 78 (see Sequence Listing; Paragraph 0055), which is 100% identical to instant SEQ ID NO: 4.
Bancel et al. teach SEQ ID NO: 104284, which is 86.3% identical to instant SEQ ID NO: 24 (see Sequence Listing).
Shaner et al. teach SEQ ID NO: 1 , which is 99.4% identical to instant SEQ ID NO: 13 (see Sequence Listing).
A person having ordinary skill in the art would have been motivated to combine the teachings of Tan et al., Minshull and Theodorou, Ast et al., Lakshmanan et al., Brandon and Thomas, Bancel et al., and Shaner et al. in order to develop a protease biosensor comprising one or two fluorescent proteins, a degron, a 5’ UTR, and a cleavage site. The addition of the specific protease recognition site taught by Tan et al. to the expression vector taught by Minshull and Theodorou would allow for the generation of a construct where the cleavage site, if placed between the single fluorescent reporter and the proteasome degradation signal, would allow for the determination of the presence of a particular protease since, if the degron is not cleaved off the fluorescent protein by the target protease, the fluorescent reporter will be degraded and there will not be any fluorescence detected. The use of the self-cleaving peptide, as taught by Minshull and Theodorou, and degron, as taught by Lakshmanan et al., with the fluorescent fusion substrate construct, as taught Tan et al., would allow for the creation of a construct where the presence of the self-cleaving peptide between the two fluorescent reporters would allow for monitoring of the efficiency of the introduction of the vector and measuring the protease activity, as one reporter would be degraded in the absence of the target protease while the signal from the other reporter would be unaffected. The dual fluorescence would increase the sensitivity and reliability of the protease activity assay, particularly when used for measuring the replication of a virus or to identify and/or screen candidate protease inhibitors specific for a target protease, making the assay more efficient and cost-effective. As such, the combinations of these teachings render the inventions encompassed by said claims obvious and thus render instant Claims 1, 5, 9, 15, 19-20, 36, 38, 41, 47-48, 50, 53, and 57 obvious over the prior art.
Such modifications, combining prior art elements according to known methods in order to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 1, 5, 9, 15, 19-20, 36, 38, 41, 47-48, 50, 53, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Claims 4, 7, 13, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. (US 2005/0214890 A1, Published 29 September 2005), Minshull and Theodorou (US 2015/0225468 A1, Published 13 August 2015), Ast et al. (US 2017/0247769 A1, Published 31 August 2017), Lakshmanan et al. (US 2021/0060185 A1, earliest Priority Date 28 August 2019), Brandon and Thomas (US 2008/0274988 A1, Published 06 November 2008), Bancel et al. (US 2014/0010861 A1, Published 09 January 2014), and Shaner et al. (U.S. Patent No. 10,221,221 B2, Issued 05 March 2019), as applied to claims 1, 5, 9, 15, 19-20, 36, 38, 41, 47-48, 50, 53, and 57 above, and further in view of Meyer and Vignuzzi (US 2023/0257734 A1, earliest Priority Date 03 July 2020), Agrawal et al. (WO 2021/173865 A2, earliest Priority Date 25 February 2020), and Tanaka et al. (2012) (cited on IDS filed on 10 Mach 2023)
Tan et al., Minshull and Theodorou, Ast et al., Lakshmanan et al., Brandon and Thomas, Bancel et al., and Shaner et al. do not teach a vector comprising a 5’UTR and a cleavage site, wherein the 5’UTR comprises the 5’ UTR of a SARS-CoV-2 genome and wherein the cleavage site is specifically cleaved by a 3C-like protease, a papain-like protease, or a caspase. They also do not teach a method of detecting SARS-CoV-2 infection in a sample from a subject, wherein the sample comprises cells from the subject, comprising introducing an effective amount of the vector encoding the biosensor to the cells in the sample and measuring a signal from the reporter protein.
Tan et al., however, does teach a method of detecting SARS-CoV-1 in a sample via the activity of the viral protease, such as the 3C-like protease, and/or identifying specific inhibitors of said protease (see Paragraphs 0015, 0054-0055, 0077-0078, 0133).
Meyer and Vignuzzi teach a method for the detection of a virus, such as SARS-CoV-2, in a biological sample using a reporter protein, such as GFP, as a biosensor designed for specific activation by viral components, such as a viral protease (see Abstract; Paragraphs 0005, 0010, 0013, 0058, 0081). Meyer and Vignuzzi also teach a vector comprising a nucleic acid construct encoding said reporter protein and a cleavage site, wherein said cleavage site is recognized by a SARS-CoV-2 protease, such as 3C-like protease, specifically, SEQ ID NO: 136, which is 100% identical to instant SEQ ID NO: 6. Additionally, Meyer and Vignuzzi teach cells comprising said vector (see Paragraphs 0060-0061). Furthermore, Meyer and Vignuzzi teach a method of detecting SARS-CoV-2 infection in a sample comprising measuring a signal from the reporter protein (see Paragraphs 0004, 0098, 0112; Figure 14).
Agrawal et al. teach a protease biosensor for detecting coronaviruses, such as SARS-CoV-2, wherein the biosensor comprises a degron, such as ubiquitin, a cleavage site specifically cleaved by a papain-like protease, and a fluorescent reporter molecule (see Abstract; Paragraphs 0093-0094, 0138).
Tanaka et al. teach that the 5’ UTR of SARS-CoV-1 RNA protects viral mRNA from the host translational shutoff caused by the viral NSP1 protein (see Abstract).
A person having ordinary skill in the art would have been motivated to modify the teachings of Minshull and Theodorou, Ast et al., Lakshmanan et al., Brandon and Thomas, Bancel et al., and Shaner et al. with those of Meyer and Vignuzzi, Agrawal et al., and Tanaka et al. in order to develop a protease biosensor for detecting SARS-CoV-2 in a sample. The protease activity assay system and expression vector taught by Tan et al. is specifically contemplated for use in the rapid diagnosis for the efficient detection and control of infectious diseases, such as SARS-CoV-1, as viral proteases are generally essential for infection of host cells by viruses and viral propagation in said cells. As such, it would have been obvious for a skilled artisan to try this assay with SARS-CoV-2, given how closely related the two viruses are. The inclusion of a 5’ UTR in the vector construct of Meyer and Vignuzzi or the protease activity assay system and expression vector taught by Tan et al. could serve as the protein translation initiation site if it contains a Kozak sequence, for example, as disclosed by Lakshmanan et al., and possibly contain a Kozak sequence which can increase translation efficiency. The dual fluorescent reporter proteins of Ast et al. would allow for the distinction between two different signals which can be measured, enhancing the range of the biosensor disclosed by Meyer and Vignuzzi or the protease activity assay system and expression vector taught by Tan et al. The protease biosensor comprising ubiquitin disclosed by Agrawal et al. would allow for the degradation of one of the fluorescent reporter proteins disclosed by Ast et al., Meyer and Vignuzzi, or Tan et al., which would in turn allow for a measurable change in the signal produced by one of the fluorescent proteins, which would further enable a distinction between the two different fluorescent proteins used and signal a change in the amount of viral replication. Given the teachings of Tanaka, it would have been obvious for a skilled artisan to try the SARS-CoV-2 5’ UTR as a means for avoiding translational shutoff of the claimed vector in cells being tested for the presence of SARS-CoV-2, due to how closely related SARS-CoV-1 and SARS-CoV-2 are. The combination of these teachings would have allowed for the development of a sensitive and specific biosensor to quickly identify samples containing SARS-CoV-2 or compounds which can inhibit SARS-CoV-2 protease activity and therefore replication. As such, the combinations of these teachings render the inventions encompassed by said claims obvious and thus render instant Claims 4, 7, 13, and 52 obvious over the prior art.
Such modifications, combining prior art elements according to known methods in order to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 4, 7, 13, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Minshull and Theodorou (U.S. Patent No. 9,493,521 B2, Issued 15 November 2016)
Minshull and Theodorou teach SEQ ID NO: 116, which is 100% identical to instant SEQ ID NO: 15. This reference has not been utilized, as rejection would have been redundant to those set forth above.
Lin et al. (US 2023/0192660 A1, earliest Priority Date 08 May 2020)
Lin et al. teach a method of using a reporter polypeptide in an assay for protease inhibition of coronavirus protease activity by an agent. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671