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 .
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). The examiner has noted that an amino acid sequence is provided at the end of pg. 3 of the specification without an accompanying sequence identifier. There is also a recitation of KLVFF in claim 2 without an accompanying sequence identifier.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, 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.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. The examiner notes that depictions of amino acid sequences appear in figures 6A, 7, 8B, 8D, 11A, 13, 14, 16, 17, 36A, 41, 42, 43A-C, 44A-C, and 45A-C and these are not accompanied by sequence identifiers either in the drawing or in the associated Brief Description of the Drawings sections.
Required response – Applicant must provide:
Amended 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 (i.e., “SEQ ID NO:X” or the like) 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.
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.
Drawings
The drawings are objected to because of the following informalities:
In each of Figures 20B-F, graphs containing two curves are present. However, both curves are very similar in color and pattern; thus, a reader is unable to distinguish which curve belongs to which sample. Therefore, it is not possible for a reader to clearly interpret this figure. Furthermore, Figure 20B appears to be missing a figure legend or key indicating which curve belongs to which sample.
In each of figures 27A-C, bar graphs are presented comparing cell viability values for five different experimental groups. However, the formatting of each bars is too similar to each other such that a reader is unable to assign a given bar to the appropriate experimental group.
Appropriate correction is required.
Specification
The abstract of the disclosure is objected to because of the following informalities:
There is a period and extra spaces present at the beginning of the abstract. These should be removed.
The abstract uses the term “AIEgens” multiple times when referring to a singular noun. The examiner understands this term to be the plural form of the term in the art AIEgen. The singular form of the term should be substituted in each instance.
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 disclosure is objected to because of the following informalities:
Examples 1 and 3 contain several references to figures such as “S1” or “S2.” However, no figures with those labels are disclosed in the instant specification.
Appropriate correction is required.
Claim Objections
Claims 2, 3, 5, and 8 are objected to because of the following informalities:
Claim 2 contains a grammatical error. It appears there should be another word such as “which” or “that” between “PyTPE” and “has.”
Claim 2 contains an unpaired parentheses. One is present before “the main protease,” and no paired closing parentheses is provided.
Claim 3 contains an unpaired parentheses. One is present before “the main protease,” and no paired closing parentheses is provided.
Claim 5 repeats the word “infected” twice at the end of the second to last line and the start of the last line. One of these instances should be removed.
Claim 8 contains an unnecessary “in” at the end of the second to last line. The examiner suggests removing this word.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3-5 and 8 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.
Claim 3 recites a nanofiber comprising a plurality of synthetic PSGMR, which is interpreted by the examiner to be equivalent to the structure described by PyTPE-(Pra)KLVFFGGGSAVLQ/SGFRKMAGGGRRRRRR. However, the instant specification does not appropriately disclose such nanofibers. While the specification does disclose nanofibers and their effects on cells, the specification teaches that the nanofibers possess a different structure (PyTPE-(Pra)KLVFFGGGSAVLQ, abbreviated as PSG) and that this is formed as a result of the cleavage of PSGMR by Mpro (see Figure 41 and Example 3). Furthermore, while methods of exposing cells to PSGMR nanoparticles and PSG nanofibers are disclosed (claim 5), no such disclosure is provided for exposing cells to PSGMR nanofibers. Additionally, while pharmaceutical compositions (claim 4) and methods of using the pharmaceutical composition (claim 8) are disclosed in the specification, these are done so by describing the preparation of a composition comprising PSGMR and administering that composition. However, for the above stated reasons, the composition and the method of use are taught as containing and using PSGMR, which is described by the applicant to form loose nanoparticles and not nanofibers. Accordingly, there is insufficient description to convey to one skilled in the relevant art, at the time the application was filed, had possession of nanofibers, pharmaceutical compositions of such nanofibers, and methods of use of such nanofibers and nanofiber compositions as currently claimed. Therefore, claims 3-5 and 8 are rejected. For the purpose of examination, the scope of claim 3-5 and 8 will be limited to PSG nanofibers formed as a result of PSGMR cleavage rather than PSGMR nanofibers themselves.
Claim 5 is 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 inhibiting the growth of a SARS-CoV-2 infected cell, treating or preventing SARS-CoV-2 replication, optionally intracellular SARS-CoV-2 replication, does not reasonably provide enablement for inhibiting the growth of cells infected by other viruses, treating or preventing replication (intracellular or otherwise) of other viruses, or treating or preventing a viral infection in an individual in need thereof. 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.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. These factors include, but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427, F.2d 833, 839, 166 USPQ 18, 24 (1970). To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claim 5 relates to methods of using an AIEgen-containing peptide nanofiber to effect virus growth, replication, and infection.
The relative skill of those in the art who would use such compounds is high, likely that of one who has obtained at a Ph.D. or M.D.
In the art, it is understood that different viruses contain different DNA and RNA sequences encoding different genes. This results in viral proteins possessing different amino acid sequences. It is well-understood in the field of biochemistry that protein sequence is of significant importance to drug binding affinity and efficacy. This phenomenon is exemplified by the fact that different drugs are used to treat different viral infections. Thus, it is understood that a drug that works to treat cells or individuals infected by one virus does not necessarily work to treat cells or individuals infected by other viruses.
There is generally a lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970). While predictions can be made regarding how ligands will bind receptors in silico, these are inconsistent at determining if a ligand will be able to exert a pharmacological effect in a living biological subject. Furthermore, it is understood that results in in vitro systems like cell culture do not always translate to living organisms. More specifically, Han (Han, Y. J.; et al., Theranostics, 2021) analyzed the literature of in vitro, in vivo, and clinical trial work related to SARS, MERS, and SARS-CoV-2 and conclude that “potential effects seen in in vitro studies have not translated in positive in vivo or clinical studies” (pg. 1226, left column, first paragraph).
The breadth of the claims
Claim 5 is broad insofar as the claim includes in its scope methods for using the nanofiber of claim 3 on any virus or a cell infected by any virus. While SARS-CoV-2 is provided as an optional limitation, the full scope of the claim includes all other viruses. Furthermore, the scope of claim 5 is also broad in the sense that it is drawn to methods having varying effects, including inhibiting cell growth, preventing virus replication, and treating or preventing infection in an individual. The examiner notes that the scope of preventing replication and infection includes preventing exposing cells not already containing a virus or viral proteins to the nanofiber of claim 3 and exerting an effect preventing infection of those cells by any virus.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides little direction or guidance for practicing the claimed invention in its “full scope.” Examples 3 and 4 of the specification provides examples of exposing cells to PSGMR peptide conjugates. In these examples, it is taught that only SARS-CoV-2 infected or Mpro-expressing cells exhibit inhibited cell growth when exposed to PSGMR. No other viruses are taught and no teachings of treating or preventing infection in an individual or a cell are provided. The only other guidance provided for the practice of this method is very broad, such that it could apply to nearly all pharmaceutical compounds.
The quantity of experimentation necessary
Experimentation to determine an effective amount of a compound used to impact SARS-CoV-2 infected cells to use for other viruses would be significant. There are a vast number of viruses known to the biomedical research field, each possessing different biological properties. Furthermore, experimentation to determine a therapeutically or diagnostically effective amount of material to administer to an individual is be significant, especially when the guidance thus far is solely in vitro cell culture models. Furthermore, determining if any given compound is effective for treatment of certain diseases may span long periods of time. Additionally, prevention studies may take even longer.
Because of the known state of the art, and in the absence of experimental evidence and working examples, it is apparent that the amount of experimentation required to determine how to use the nanofiber of claim 3 to perform all of the claimed methods with viruses that are not SARS-CoV-2 or in living beings is very significant and unreasonable due to the nature of virus biology and the lack of predictability translating from cell culture to in vivo systems.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in its “full scope,” a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success.
Claim 8 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Wands factors are as described above. Regarding claim 8:
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claim 8 relates to methods of using a pharmaceutical composition comprising an AIEgen-containing peptide nanofiber to effect virus growth, replication, and infection in an individual.
The relative skill of those in the art who would use such compounds is high, likely that of one who has obtained at a Ph.D. or M.D.
In the art, it is understood that different viruses contain different DNA and RNA sequences encoding different genes. This results in viral proteins possessing different amino acid sequences. It is well-understood in the field of biochemistry that protein sequence is of significant importance to drug binding affinity and efficacy. This phenomenon is exemplified by the fact that different drugs are used to treat different viral infections. Thus, it is understood that a drug that works to treat one viral infection does not necessarily work to treat infection by other viruses. Furthermore, it is understood that in order to exert a biological effect in a living organism (an individual), after a molecule is administered to an individual, the organism possesses means of degrading and “clearing” the body of the administered compound, and the molecule must be present in an effective amount despite the clearance functions in the organism.
There is generally a lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970). While predictions can be made regarding how ligands will bind receptors in silico, these are inconsistent at determining if a ligand will be able to exert a pharmacological effect in a living biological subject. It is difficult to predict how a molecule will perform in a living system. Furthermore, it is understood that results in in vitro systems like cell culture do not always translate to living organisms. More specifically, Han (Han, Y. J.; et al., Theranostics, 2021) analyzed the literature of in vitro, in vivo, and clinical trial work related to SARS, MERS, and SARS-CoV-2 and conclude that “potential effects seen in in vitro studies have not translated in positive in vivo or clinical studies” (pg. 1226, left column, first paragraph).
The breadth of the claims
Claim 8 is broad insofar as the claim includes in its scope methods for using a pharmaceutical composition comprising the nanofiber of claim 3 in any individual in need thereof (note – the examiner interprets “individual” in this context to require a living animal) infected by any virus. Thus, claimed methods of inhibiting cell growth, viral replication, and infection must occur within the context of a living animal. While SARS-CoV-2 is provided as an optional limitation, the full scope of the claim includes all other viruses. Furthermore, the scope of claim 8 is also broad in the sense that it is drawn to methods having varying effects, including inhibiting cell growth in an individual, preventing virus replication in an individual, and treating or preventing infection in an individual.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides little direction or guidance for practicing the claimed invention in any scope. Examples 3 and 4 of the specification provides examples of exposing SARS-CoV-2 infected or Mpro-expressing cells to PSGMR peptide conjugates. No examples are taught in which a pharmaceutical composition is administered to an individual in need thereof. In view of Han, the presence of only cell culture studies does not provide sufficient correlation with the in vivo methods as claimed (see MPEP § 2164.02(II)). No other (non-SARS-CoV-2) viruses are taught and no teachings of treating or preventing infection in an individual or cell are provided. The only other guidance provided for the practice of this method is very broad, such that it could apply to nearly all pharmaceutical compounds.
The quantity of experimentation necessary
Experimentation to determine an effective amount of a compound used to impact SARS-CoV-2 infected cells to use for other viruses in the context of a living animal would be significant. There are a vast number of viruses known to the biomedical research field, each possessing different biological properties. Furthermore, experimentation to determine a therapeutically or diagnostically effective amount of material to administer to an individual is be significant, especially when the guidance thus far is solely in vitro cell culture models. Furthermore, determining if any given compound is effective for treatment of certain diseases may span long periods of time. Additionally, prevention studies may take even longer.
Because of the known state of the art, and in the absence of experimental evidence and correlative working examples, it is apparent that the amount of experimentation required to determine how to use the composition of claim 4 to perform all of the claimed methods in living beings is very significant and unreasonable due to the nature of virus biology , drug biology, and the lack of predictability translating results from cell culture to in vivo systems.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in any embodiment, a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-11 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 formatted in a way that results in multiple possible interpretations. Feature (a) is understood to describe both the generic EGTP structure and introduce feature E. As it is written, the combination of features (a), (b), (c), and (d) would result in a product that comprises EGTP plus G, T, and P. Though in view of the disclosure as a whole, it appears the applicant discloses EGTP comprising the claimed E, G, T, and P features. These are two different possible scopes for this claim. Due to the uncertainty in the scope of the claim, it is considered indefinite. The examiner will interpret the scope of claim 1 to be a product of manufacture, synthetic peptide, or polypeptide that can be described as EGTP comprising features E, G, T, and P. The examiner suggests amending the claim to move the generic description of the full EGTP molecule from claim element (a) to a location prior to feature (a) and only containing the description of feature E in (a).
The term “accurate” in claim 1 is a relative term which renders the claim indefinite. The term “accurate” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the bounds of "accurate inhibitor screening" are. For the purpose of examination, any suitability for inhibitor screening will be interpreted to read on this limitation.
Claim 1, feature (d) recites “a TMPRSS2-responsive peptide (QAR, T).” It is unclear whether the contents of the parentheses are meant to be equal in scope (i.e., limiting) to the phrase before the parentheses. Therefore, the scope of the claim is considered indefinite. For the purpose of examination, the examiner will interpret the scope of this feature in the claim to be restricted to just the QAR sequence (glutamine-alanine-arginine), as feature (d) of claim 1 also later recites and requires the presence of a QAR sequence in the modified peptide structure.
Claim 1, feature (d) recites “a positive charged AIEgens (PyTPE, P).” It is unclear whether the contents of the parentheses are meant to be equal in scope (i.e., limiting) to the phrase before the parentheses. Therefore, the scope of the claim is considered indefinite. For the purpose of examination, the examiner will interpret the scope of this feature in the claim to be restricted to just PyTPE, as feature (a) of claim 1 also requires the presence of PyTPE in the modified peptide structure.
Claim 2, feature (b) recites “a self-assembling peptide (KLVFF, S)…” It is unclear whether the contents of the parentheses are meant to be equal in scope (i.e., limiting) to the phrase before the parentheses. Therefore, the scope of the claim is considered indefinite. For the purpose of examination, the examiner will interpret the scope of this feature in the claim to be limited to the KLVFF sequence, as this sequence is required within the previously recited and required SEQ ID NO 18 in the same claim. Furthermore, claims 3-11 are rejected due to their dependence on claim 2.
Claim 2, feature (d) recites “a Mpro-responsive peptide (SAVLQ/SGFRKMA (SEQ ID NO 6), M)” It is unclear whether the contents of the parentheses are meant to be equal in scope (i.e., limiting) to the phrase before the parentheses. Therefore, the scope of the claim is considered indefinite. For the purpose of examination, the examiner will interpret the scope of this feature in the claim to be limited to SEQ ID NO 6, as this sequence is required within the previously recited and required SEQ ID NO 18 in the same claim. Furthermore, claims 3-11 are rejected due to their dependence on claim 2.
The term “bright” in claim 2 is a relative term which renders the claim indefinite. The term “bright” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the bounds of "bright yellow fluorescence" are. For the purpose of examination, any degree of yellow fluorescence will be interpreted to read on this limitation. Furthermore, claims 3-11 are rejected due to their dependence on claim 2.
The term “excellent” in claim 2 is a relative term which renders the claim indefinite. The term “excellent” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the bounds of "excellent biocompatibility" are. For the purpose of examination, any degree of biocompatibility will be interpreted to read on this limitation. Furthermore, claims 3-11 are rejected due to their dependence on claim 2.
The term “good” in claim 2 is a relative term which renders the claim indefinite. The term “good” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the bounds of "good photostability" are. For the purpose of examination, any degree of photostability will be interpreted to read on this limitation. Furthermore, claims 3-11 are rejected due to their dependence on claim 2.
Claim 2 recites the limitation "the Mpro-responsive modular peptide" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Therefore, the claim is indefinite. For the purpose of examination, the examiner will interpret this to mean an Mpro-responsive modular peptide. Furthermore, claims 3-11 are rejected due to their dependence on claim 2.
Claim 9 recites “the method of claim 2.” However, claim 2 is drawn to a product of manufacture, peptide, or polypeptide. Claim 2 is not drawn to a method. Therefore, it is unclear what the scope of claim 9 is, rendering claim 9 indefinite. For the purpose of examination, the examiner will interpret claim 9 to be drawn to a product of manufacture, peptide, or polypeptide; as is supported by the original claims as filed.
Claim 10 recites “the method of claim 2.” However, claim 2 is drawn to a product of manufacture, peptide, or polypeptide. Claim 2 is not drawn to a method. Therefore, it is unclear what the scope of claim 10 is, rendering claim 10 indefinite. For the purpose of examination, the examiner will interpret claim 10 to be drawn to a product of manufacture, peptide, or polypeptide; as is supported by the original claims as filed.
The term “loose” in claim 10 is a relative term which renders the claim indefinite. The term “loose” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the bounds of "loose nanoparticles" are. For the purpose of examination, any nanoparticle form will read on this limitation.
Claim 11 recites “the method of claim 2.” However, claim 11 is drawn to a product of manufacture, peptide, or polypeptide. Claim 2 is not drawn to a method. Therefore, it is unclear what the scope of claim 11 is, rendering claim 11 indefinite. For the purpose of examination, the examiner will interpret claim 11 to be drawn to a product of manufacture, peptide, or polypeptide; as is supported by the original claims as filed.
The term “strong” in claim 11 is a relative term which renders the claim indefinite. The term “strong” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the bounds of "strong yellow fluorescence" are. For the purpose of examination, any degree of yellow fluorescence form will read on this limitation.
Claim 11 recites the limitation "the nanoparticle surface" in line 3. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of or requirement for a nanoparticle in claim 11 or claim 2 (upon which claim 11 depends). Therefore, the claim is rendered indefinite, as it is unclear to what nanoparticle is being referred. The examiner notes the description of a nanoparticle in claim 10. For the purpose of examination, the examiner will interpret claim 11 to depend upon claim 10.
Claim 11 recites the limitation "PSG" in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation or description of the abbreviation “PSG” in claim 11 or claim 2 (upon which claim 11 depends). Therefore, the claim is rendered indefinite, as it is unclear to what PSG is. The examiner notes that claim 2 describes component parts signified by the letters P, S, and G. For the purpose of examination, the examiner will interpret PSG in this claim to refer to a covalently coupled conjugate of PyTPE, a self-assembling peptide, and trimylglycine.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cheng 2023 (Cheng, Y.; et al., Anal. Chem., published February 8, 2023).
Cheng 2023 teaches a peptide conjugated probe referred to as EGTP (pg. 3789, Abstract). The EGTP conjugate is described by the structure composition EEEEEEEEEGGGQAR/GG(Pra)-PyTPE (pg. 3791, Figure 1a), wherein the slash represents a TMPRSS2 cleavage position, Pra represents a propylargylglycine linker, and PyTPE represents a tetraphenylethene pyridinium AIEgen (pg. 3792, Design, Synthesis, and Characterization of EGTP and Its Derivatives; and pg. 3789, Introduction). Cheng 2023 teaches TMPRSS2-selective imaging in cancer cells with EGTP (pg. 3793, Figure 3). Cheng 2023 also describes EGTP as surface-potential-tunable (pg. 3796, Conclusions). Cheng 2023 further teaches using EGTP for accurate TMPRSS2 inhibitor screening (pg. 3795, Figure 5).
Regarding claim 1, the EGTP conjugate of Cheng 2023 has the structure EEEEEEEEEGGGQAR/GG(Pra)-PyTPE (pg. 3791, Figure 1a). The nine repeats of glutamic acid read on the polyglutamic acid requirement. This is followed by a trimylglycine group, then a sequence wherein the residues QAR are present and a TMPRSS2 cleavage site is present after the QAR sequence (pg. 3792, Design, Synthesis, and Characterization of EGTP and Its Derivatives; and pg. 3789, Introduction). Cheng 2023 also teaches the PyTPE as a positively charged AIEgen (pg. 3790, Scheme 1).
Claims 2-5, and 9-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cheng 2022 (Cheng, Y.; et al, ACS Nano, published July 25, 2022).
Cheng 2022 teaches a peptide conjugated probe referred to as PSGMR (pg. 12305, Abstract). The PSGMR conjugate is described by the peptide sequence PyTPE-(Pra)KLVFFGGGSAVLQ/SGFRKMAGGGRRRRRR (pg. 12307, Figure 1e), wherein the slash represents an Mpro (SARS-CoV-2 main protease, pg. 12305, Introduction) cleavage site (pg. 12307, right column).
Cheng 2022 teaches using PSGMR for imaging mitochondria (pg. 12309, Figure 2) and inhibition of virus infected cells (pg. 12311, Figure 4).
Regarding claim 2, the PSGMR conjugate of Cheng 2022 has the structure PyTPE-(Pra)KLVFFGGGSAVLQ/SGFRKMAGGGRRRRRR (pg. 12307, Figure 1e). This contains the PyTPE AIEgen, the sequence KLVFF, which is described as a self-assembling peptide (pg. 12307, right column), two trimylglycine spacers, the sequence SAVLQ/SGFRKMA wherein the slash represents an Mpro cleavage site (pg. 12307, right column), and hexamolyarginine. In this conjugate, all these components are covalently coupled.
Regarding claim 3, Cheng 2022 teaches nanofibers formed from the product of the PSGMR conjugate after Mpro cleavage (Scheme S1).
Regarding claim 4, Cheng 2022 teaches preparing solutions of the peptide probe in phosphate buffered saline and providing them to HEK 293T cells to study their effects (pg. 12314, Incubation of Living Cells with Probes). The examiner notes that the claims and instant disclosure do not define a pharmaceutical composition other than that it contains the peptide nanofiber. No additional components are required in the scope of the claim. Thus, the examiner interprets the composition of the PSGMR peptide probes in PBS to be a pharmaceutical composition.
Regarding claim 5, Cheng 2022 teaches using nanofibers formed from the product of the PSGMR conjugate after Mpro cleavage for inhibition of SARS-CoV-2 cells (Scheme S1 and Figure 5).
Regarding claim 9, the examiner interprets this claim to be a product-by-process claim. Per MPEP § 2113, the patentability of a product does not depend on its method of production. Nonetheless, in this case, Cheng 2022 teaches coupling the components of the PSGMR conjugate by Fmoc-based solid-phase peptide synthesis and copper-catalyzed azide-alkyne click reaction (pg. 12308, left column, second paragraph; and Scheme S3).
Regarding claim 10, Cheng 2022 teaches that PSGMR forms loose nanoparticles in the absence of Mpro (pg. 12308, left column, first paragraph).
Regarding claim 11, Cheng 2022 teaches that Mpro cleavage separates PSG from the hexamolyarginine, leading to PSG aggregation and nanofiber formation with strong yellow fluorescence (Scheme S1).
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.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Shrimp (Shrimp, J. H.; et al., ACS Pharmacol. Transl. Sci., 2020) in view of Cheng 2016 (Cheng, Y.; et al., Anal. Chem., 2016), Weinstain (Weinstain, R.; et al., J. Am. Chem. Soc., 2013), and Chen (Chen, X.; et al., Adv. Drug. Delivery Rev., 2013).
Shrimp teaches a method of screening inhibitors for potential COVID-19 treatments (pg. 997, Abstract). The method of Shrimp uses a Boc-Gln-Ala-Arg-AMC (QAR-AMC) fluorescent probe (pg. 998, Figure 1). This probe is cleaved between the QAR sequence and AMC fluorophore by TMPRSS2, a human transmembrane protease that is a target of SARS-CoV-2 (Figure 1; and pg. 997, Introduction). The QAR-AMC conjugate displays less fluorescence than the cleaved product (Figure 1 caption). Shrimp teaches that this protease-responsive fluorescent probe effectively identifies clinically-approved TMPRSS2 inhibitors as inhibitors (Figure 3). Shrimp describes this method as being amenable to high throughput drug screening (pg. 1004, right column, second paragraph).
Shrimp does not teach a protease-responsive fluorescent peptide conjugate comprising PyTPE, polyglutamic acid, and a trimylglycine linker.
Cheng 2016 teaches a protease-responsive fluorescent peptide conjugate (pg. 8913, Abstract). The conjugate contains a PyTPE AIEgen molecule coupled to the peptide by a propylargylglycine residue and another glycine adjacent to it (Figure 1). The peptide also contains a LGLAG sequence that is cleaved by MMP-2 protease (pg. 8914, left column, second paragraph). Cheng 2016 teaches that this fluorescent probe enables visualization of MMP-2 active cells (Figures 3-6). Cheng 2016 also teaches that PyTPE shows negligible cytotoxicity (pg. 8917, right column, first paragraph).
Weinstain teaches activatable cell-penetrating peptides (pg. 874, Abstract). Weinstain teaches that a polycationic (9xArg) peptide is cell penetrative and that a polyanionic (9xGlu) peptide prevents cell penetration (pg. 874, left column, second paragraph; and Figure 1). Weinstain teaches that linking the 9xArg to the 9xGlu prevents 9xArg cell penetration until the linker is cleaved (Figure 1 and Figure 2).
Chen teaches commonly used linkers in fusion proteins (pg. 1357, Abstract). Chen teaches that linkers can provide length, hydrophobicity, or secondary structure (Table 1) in fusion proteins. Among the linkers taught by Chen to be common are polyglycine linkers, including triglycine, which allow for flexibility, adjusted spacing between domains, and increased stability (Table 2 and Table 3).
A person of ordinary skill in the art would recognize that both Shrimp and Cheng 2016 teach protease-responsive fluorescent peptide probes. It would be recognized that the fluorophores of these two probes could be substituted, as they perform the same function in each instance. It would also be recognized that Weinstain and Chen teach useful modifications to peptide chains to impart desirable functions for biological use.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the fluorescent peptide probe of Shrimp with the substitution to the PyTPE fluorophore of Cheng 2016, as it performs the same function in the same way (MPEP § 2143(I)(B)), the addition of triglycine linkers, taught by Chen to improve peptide flexibility and stability (MPEP § 2143(I)(C)), and the addition of a 9xGlu polyanionic peptide, as taught by Weinstain to prevent unwanted cell penetration (MPEP § 2143(I)(C)). This combination would have yielded the predictable outcome of a fluorescent peptide probe comprising a polyglutamic acid, trimylglycine linker, QAR sequence, and PyTPE.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because each of these arts teach peptide conjugates. Each of these modifications can be made by linking amino acids along the peptide backbone in the canonical manner.
The skilled artisan would have been motivated to make these modifications because PyTPE provides bright yellow fluorescence, triglycine provides increased stability, and polyglutamic acid prevents undesired cell penetration, as taught by Cheng 2016, Chen, and Weinstain, respectively. These are each modifications that can improve the use of the probe for screening TMPRSS2 inhibitors.
Pertinent Art
As pertinent art, the examiner cites Tang (US 10,753,941 B2). Tang teaches a fluorescent AIEgen probe (Abstract). More specifically, Tang teaches a protease-responsive peptide-AIEgen conjugate, AcDEVDK-TPE (column 79, Example 25, boxed structure). This structure is an AIEgen fluorophore TPE that increases in fluorescence upon aggregation (Column 14, last paragraph) conjugated to a short peptide. Tang also teaches that the DEVD peptide sequence can be selectively cleaved by caspase-3/caspase-7 (column 11, lines 60-63). Tang further teaches that cleavage of the conjugate by the caspase enzymes results in increased fluorescence, enabling the study of protein activity in solutions and cells (column 54, last paragraph; and column 55, last paragraph through column 56, first paragraph). The examiner notes that while Tang teaches an example of a protease-responsive AIEgen-peptide conjugate, Tang does not teach the specific AIEgen PyTPE or the use of SARS-CoV-2 related protease cleavage sequences, glycine spacers, polyglutamic acid, or hexamolyarginine groups in such a peptide conjugate.
Conclusion
No claim is allowed.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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