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 .
Claim Status
Claims 1-12, 15-17, 20, and 22-25 are pending. Claims 8, 12, 15, 17, 20, 22 and 24 are currently amended.
Priority
The instant application is the 371 national stage entry of PCT/CN2023/075042, filed 2/8/2023, which claims priority to PCT/CN2022/075738, filed 2/9/2022. The priority date of 2/9/2022 is acknowledged.
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 IDS filed on 8/8/2024 is under consideration.
Drawings
The drawings are objected to because: 1) in Figure 7 it’s not clear what is being depicted because there are no X or Y axes labels; and 2) the key of Figure 11 is too small to read:
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. 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.
Nucleotide and/or Amino Acid Sequence Disclosures
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 specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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.
See [0090, 00149, 00158]
Specification
The use of the terms ALIGN, MEGALIGN, DNASTAR ([0060]); NANODROP ONE ([00148, 00149, 00152, 00179]); SUPERDEX75 ([00153]); TRITON X-100 ([00167]); BIOPIPELINE LIVE ([00189]) which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 2, 3, 7, 22, and 25 are objected to because of the following informalities: Improve the readability of the above claims by introducing the following amendments:
Claim 2: “…the phase separation associated disease is a phase separation associated vision disorder.”
Claim 3: “…the phase separation associated vision disorder is a cataract.”
Claim 22: “The method of claim 1, wherein… a wash for an anterior chamber…”
Claim 25: “A kit for treating phase separation associated diseases… such that the administration treats the phase separation associated disease,…” (emphasis added).
Additionally, in claim 7 remove the references to RJK001, RJK002, and RJK012.
Appropriate correction is required.
Claim Interpretation
Claims 1, 23, and 25 each recite a polypeptide that has a hydrophilic and a hydrophobic segment, wherein the hydrophilic segment is at least 50% Asp, Glu, Lys or Arg and the hydrophobic segment is at least 50% Tyr, Phe, Trp, Leu, Ile, Val, Met, Pro, Ala or Cys. The hydrophilic segment is being interpreted as any amino acid sequence wherein at least 50% of the total amino acids is one of the four listed amino acids, in any order, and wherein the remaining amino acids can be any other amino acid. Similarly, the hydrophobic segment is being interpreted as any amino acid sequence wherein at least 50% of the total amino acids is one of the 10 amino acids listed above, in any order, and wherein the remaining amino acids can be any amino acid. Moreover, the hydrophilic and the hydrophobic segments are oriented relative to each other, thereby resulting in a first segment that is N-terminal to the second and the second segment is C-terminal to the first. This interpretation also applies to claim 8.
Moreover, the limitation “capable of reversing phase separation” is being interpreted as a function inherent to the sequence of the polypeptide.
Claim 15 recites that the polypeptide is further fused with a linker, which is being interpreted as the linker is connected to the polypeptide so as to further join said polypeptide to another moiety and not where the linker is interspersed between the hydrophilic and the hydrophobic segments.
Claim Rejections - 35 USC § 112
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 1-12, 15-17, 20, 22-25 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 claims 1, 23, and 25 each recite that the polypeptide comprises a hydrophilic and a hydrophobic segment, each of which has a length of 10-20 amino, wherein the hydrophilic segment is at least 50% Asp, Glu, Lys or Arg and the hydrophobic segment is at least 50% Tyr, Phe, Trp, Leu , Ile, Val, Met, Pro, Ala or Cys, either the hydrophilic segment is at the N-terminus and the hydrophobic segment is at the C-terminus or vice versa, and the polypeptide has a total length of 20-60 amino acids. Claim 8 similarly recites that the polypeptide comprises a hydrophilic segment of length 10-17 amino acids among which at least 60% are Asp, Glu, Lys, or Arg and the hydrophobic segment having a length of 10-12 amino acid residues among which at least 35% are Tyr, Phe, Leu, or Val, wherein the polypeptide has a total length of 20-28 amino acids.
The scope of each of these claims is indefinite for two reasons.
First, the cutoff between the hydrophilic and the hydrophobic segments of the polypeptide is unclear; in other words, one skilled in the art reading the claim would not immediately recognize where the hydrophilic segment started and stopped in relation to where the hydrophobic segment started and stopped.
Second, the claim language indicates that the polypeptide is open to additional elements not expressly recited based on the transitional phrases “comprising” and “has” but also recites strict length limitations, such as 10-20 or 10-17 amino acids for each of the hydrophilic and hydrophobic segments and 20-60 or 20-28 amino acids overall for the full-length polypeptide. Thus, it is unclear whether the full-length polypeptides of the claim are limited to polypeptides consisting of 20-60 or 20-28 amino acids of the specified amino acid composition or is open to full-length polypeptides comprising the specified amino acid composition regardless of length.
For purposes of examination, the polypeptide will be interpreted as comprising a segment that has at least 50% Asp, Glu, Lys or Arg (hydrophilic segment) and a segment has at least 50% Tyr, Phe, Trp, Leu, Ile, Val, Met, Pro, Ala or Cys (hydrophobic segment), regardless of length.
Further, by virtue of their dependency on claims 1, 23, and 25, claims 2-12, 15-17, 20, 22 and 24 are also hereby rejected for this same reasoning.
Additionally, claims 5-7 and 10 each recite a group of hydrophilic or hydrophobic amino acid sequences or a sequence having at least 90% identity thereto or 1-5 residue differences therefrom. The scope of each of these claims is indefinite because it’s unclear whether polypeptides meeting the limitations of the claims must be 90% identical to a recited SEQ ID NO or can be less than 90% identical. For example, claim 5 recites SEQ ID NO: 21, which is 8 residues in length. A polypeptide exhibiting 90% identity to SEQ ID NO: 21 would only differ by one amino acid, but the claim also allows for up to 5 amino acid differences, which would result in only 37.5% sequence identity (8-5=3/8*100=37.5%). For purposes of examination, the claims are being interpreted as being limited to polypeptides with 90% or greater identity.
Moreover, claim 20 recites the polypeptide, the polynucleotide encoding said polypeptide, or the vector encoding said polynucleotide, is administered “ocularly (eye drops, insert, injection, or implant).” This limitation renders the scope of the claim indefinite because it’s unclear whether ocular administration is as broad as is covered by ocular administration or is limited to the ocular methods described in the parentheses. For purposes of examination, the claim is being interpreted as being open to administration through any ocular means.
Regarding claim 25, the phrase "(e.g., cataracts)” (emphasis added) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Additionally, the parentheses render the scope of the claim indefinite as it is unclear whether the scope is limited to cataracts or open to any/all phase separation associated diseases.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4 and 5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 4 and 5 both recite at least one SEQ ID NO that is less than 10 amino acids in length, which is the lower limit recited in parent claim 1. Thus, claims 4 and 5 do not meet all the limitations of their parent claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
First rejection – written description
Claims 1-10, 12, 15-17, 20, 22 and 23-25 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 claims are drawn to methods and kits for treating and preventing a phase separation associated disease in a subject in need thereof, the formation of a crystalline protein aggregate, and the phase separation of crystallin protein in a cell, comprising administering a polypeptide comprising a hydrophilic and a hydrophobic segment, wherein the hydrophilic segment is at least 50% Asp, Glu, Lys, or Arg and the hydrophobic segment is at least 50% Tyr, Phe, Trp, Leu, Ile, Val, Met, Pro, Ala, or Cys, wherein the polypeptide is capable of reversing or inhibiting phase separation. Effectively, the claims are drawn to a broad genus of polypeptide agents that possess the ability to inhibit the protein aggregation or phase separation of any protein.
Further, claims 5-7 and 10 recite additional limitations that allow for peptide segments or full-length sequences to exhibit 90% sequence identity to the claimed SEQ ID NO’s, which only serves to increase the breadth of the polypeptides claimed. As an example, SEQ ID NO: 1 is 41 amino acids in length; sequences having at least 90% sequence identity would require 37 of the amino acids to be maintained (i.e. 37/41*100 = 90.2%) and would allow up to 4 amino acids (i.e. 41-37 = 4) to be substituted. Consequently, there are more than 100,000 possible ways to select up to 4 residues from the 41 residues in the sequence that are free to be modified (i.e. x = n!/(r!(n-r)!)); each of which could be substituted with any of the other 19 naturally occurring common amino acids (i.e., that number multiplied by 19).
However, the claims do not disclose sufficient structure-function relationship to meet the written description requirement. The core structure or the residue(s) of the polypeptides that mediate the reversal of protein aggregation/phase separation are unknown and untested in the instant application, making it nearly impossible for one skilled in the art to determine what peptide segments must be retained in order to preserve the peptide’s functionality. To underscore this concept, Kelly et al. (US 20060058228 A1, published 3/16/2006) discuss a phage display screen to identify peptides that distinguish between well-differentiated (HCT116) and poorly-differentiated (HT29) colon cancer cell lines. Analysis of the selected library resulted in the identification of a nine amino acid, disulfide-constrained peptide having a three amino acid (arg-pro-met, “RPM”) motif that specifically binds HT29 cells ([0032]). Substituting each of RPM with alanine significantly limited or abolished the ability of the peptide to compete with wild type RPM in a binding assay, indicating that these three residues alone accounted for the ability to bind to HT29 cells ([0034]). In contrast to this example, it is unknown which residues alone or in combination facilitate the claimed peptide’s ability to reduce protein aggregation and phase separation. Thus, one cannot extrapolate the amino acid sequence requirements necessary to maintain peptide functionality.
Applicants have written description support for administration of SEQ ID NO: 1, 2, and 3 to reverse protein aggregation/phase separation of G3BP1, γD-crystallin, and γD (W42D). However, the instant application does not provide support for additional polypeptides with the claimed function.
Consequently, it is unknown whether all species of polypeptide comprising a hydrophilic and a hydrophobic segment, wherein the hydrophilic segment is at least 50% Asp, Glu, Lys, or Arg and the hydrophobic segment is at least 50% Tyr, Phe, Trp, Leu, Ile, Val, Met, Pro, Ala, or Cys, wherein the polypeptide is capable of reversing or inhibiting phase separation. Therefore, the instant specification does not provide adequate written description to possess the broad genus described above since the specification does not disclose a correlation between the necessary structure of the sequence and the claimed function to be maintained.
Second rejection – scope of enablement
Claims 1-12, 15-17, 20, and 22-25 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 treating a phase separation associated disease, does not reasonably provide enablement for prevention of a phase separation associated disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
1) Nature of the invention and 5) breadth of the claims: The invention is drawn to methods and kits for treating and preventing a phase separation associated disease in a subject in need thereof, the formation of a crystalline protein aggregate, and the phase separation of crystallin protein in a cell, comprising administering a polypeptide comprising a hydrophilic and a hydrophobic segment, wherein the hydrophilic segment is at least 50% Asp, Glu, Lys, or Arg and the hydrophobic segment is at least 50% Tyr, Phe, Trp, Leu, Ile, Val, Met, Pro, Ala, or Cys, wherein the polypeptide is capable of reversing or inhibiting phase separation.
The instant specification defines “treatment” as including preventing or alleviating a condition ([0065]). Thus, treating and preventing as claimed reads on administering a polypeptide as described above to any individual with or without a phase separation associated disease, as prevention does not require a subject in need to have a disease. However, the prior art does not teach that phase separation associated diseases can be prevented.
2) State of the prior art and 4) predictability or unpredictability of the art: The art at the time of filing recognized several types of phase separation associated diseases, including neurodegenerative disorders (i.e., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), etc.), cataracts, cancer, and SARS-Cov-2 infections (see Pg 9-13, “Pathological functions of LLPS” in Wang et al., Liquid-liquid phase separation in human health and diseases. Signal Transduct Target Ther. 2021 Aug 2;6(1):290.). However, the art recognized that these diseases cannot be prevented (see Pg 2, 5th paragraph of Moreau et al., Protein misfolding and aggregation in cataract disease and prospects for prevention. Trends Mol Med. 2012 May;18(5):273-82.; see Pg 5 of “Cataracts,” Mayo Clinic, 3/14/2026, accessed from https://www.mayoclinic.org/diseases-conditions/cataracts/symptoms-causes/syc-20353790 on 8/19/2026.; “Prevention: Can I Prevent Dementia?,” and see Pg 2 of Alzheimers.gov, accessed from https://www.alzheimers.gov/life-with-dementia/can-i-prevent-dementia on 8/19/2026.).
Thus, one skilled in the art would reasonably predict that the instant claims would not successfully prevent phase separation associated diseases.
3) The relative skill of those in the art: The relative skill of those in the art is high.
6) The amount of direction or guidance presented: At the time of filing, no direction or
guidance was presented in either the prior art or the instant specification that would enable the prevention of phase separation diseases as claimed.
7) The presence or absence of working examples: Examples 1-4 demonstrate that SEQ
ID NO: 1-3 can effectively reverse phase separation and protein aggregation of G3BP1 and γD-crystallin in in vitro and in cells, but there are no examples that demonstrate prevention of phase separation and protein aggregation.
8) The quantity of experimentation necessary: Because there are no examples in either
the prior art or the instant specification, reasonable guidance with respect to administering a composition comprising a polypeptide capable of inhibiting phase separation for preventing phase separation at large was lacking. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively prevent phase separation associated diseases.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide sufficient information to practice the claimed invention.
Third rejection – scope of enablement
Claims 1, 2, 4-12, 15-17, 20, and 22-25 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 treating a subset of phase separation associated diseases, does not reasonably provide enablement for treatment of phase separation associated diseases broadly. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
1) Nature of the invention and 5) breadth of the claims: The invention is drawn to methods and kits for treating and preventing a phase separation associated disease in a subject in need thereof, the formation of a crystalline protein aggregate, and the phase separation of crystallin protein in a cell, comprising administering a polypeptide comprising a hydrophilic and a hydrophobic segment, wherein the hydrophilic segment is at least 50% Asp, Glu, Lys, or Arg and the hydrophobic segment is at least 50% Tyr, Phe, Trp, Leu, Ile, Val, Met, Pro, Ala, or Cys, wherein the polypeptide is capable of reversing or inhibiting phase separation. The claims are written such that they include the treatment of any phase separation associated disease through administration of any polypeptide comprising a hydrophilic and a hydrophobic segment with the amino acid composition listed above. The issue is whether any and all diseases associated with protein phase separation can be treated via the instant methods as well as the degree of association required between phase separation and the disease, i.e., whether a disease indirectly associated with phase separation can also be treated.
2) State of the prior art and 4) predictability or unpredictability of the art: The art at the
time of filing recognized several types of phase separation associated diseases, including neurodegenerative disorders (i.e., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), etc.), cataracts, cancer, and SARS-Cov-2 infections (see Pg 9-13, “Pathological functions of LLPS” in Wang et al., Liquid-liquid phase separation in human health and diseases. Signal Transduct Target Ther. 2021 Aug 2;6(1):290.). However, not all of these phase separation associated diseases are directly associated with phase separation. For instance, Wang teaches the aggregation of TAR DNA-binding protein 43 (TDP-43) is characteristic of ALS; however, with one exception, most mutations in the helix of TDP-43 decrease LLPS. Other exceptions to the generally positive association between disease pathology and phase separation have also been noted in other types of proteins commonly associated with other neurodegenerative diseases and certain cancers (Pg 9-10, “Pathological functions of LLPS”).
Based on these teachings, one skilled in the art would reasonably predict that the instant claims would be incapable of treating phase separation associated diseases broadly.
3) The relative skill of those in the art: The relative skill of those in the art is high.
6) The amount of direction or guidance presented: At the time of filing, no direction or
guidance was presented in either the prior art or the instant specification that would enable one to administer a polypeptide with a hydrophilic and a hydrophobic segment to treat the breadth of phase separation associated diseases as claimed.
7) The presence or absence of working examples: The instant specification
demonstrates administration of SEQ ID NO: 1, 2, and 3 in vitro and in cells and cell lysates reverses phase separation and protein aggregation of G3BP1 and γD-crystallin, associated with p-granules and cataracts, respectively (Examples 1-4).
8) The quantity of experimentation necessary: With only a few examples in both the prior art and the instant application, reasonable guidance with respect to treating phase separation associated diseases broadly comprising administering a polypeptide with hydrophilic and a hydrophobic segments was limited. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively treat all phase separation associated diseases.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide sufficient information to practice the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 8, 20, and 22-25 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as
Being anticipated by Rosa et al. (US20130143814A1, published 6/6/2013, cited on IDS filed 8/8/2024) as evidenced by Moreau et al. (Protein misfolding and aggregation in cataract disease and prospects for prevention. Trends Mol Med. 2012 May;18(5):273-82.).
Rosa teaches methods, compositions, and devices for treating an ocular disease, disorder, or condition (Abstract).
Regarding claims 1-3 and 23, Rosa teaches the peptide SEQ ID NO: 1, which possesses a hydrophilic and hydrophobic segment (Sequence Listing):
THEAEQNDSVSPRKSRVAAQNSAEVVRCLNSALQVGCGAFACLENSTCDTDGMYDICKSF
LYSAAKFDTQGKAFVKESLKCIANGVTSKVFLAIRRCSTFQRMIAEVQEECYSKLNVCSI
AKRNPEAITEVVQLPNHFSNRYYNRLVRSLLECDEDTVSTIRDSLMEKIGPNMASLFHIL
QTDHCAQTHPRADFNRRRTNEPQKLKVLLRNLRGEEDSPSHIKRTSHESA
SEQ ID NO: 1 exhibits both hydrophilic (second shaded region, bolded residues) and hydrophobic (first shaded region, underlined residues) regions, wherein each region is at least 50% the claimed amino acid composition.
Rosa teaches said peptide can be used to treat cataracts ([0169-0170]; claim 1). As evidenced by Moreau, cataracts form through phase separation (Pg 4, 4th paragraph).
Regarding claim 8, Moreau teaches SEQ ID NO: 3 (Sequence Listing):
THEAEQNDSVSPRKSRVAAQNSAEVVRCLNSALQVGCGAFACLENSTCDTDGMYDICKSF
LYSAAKFDTQGKAFVKESLKCIANGVTSKVFLAIRRCSTFQRMIAEVQEECYSKLNVCSI
AKRNPEAITEVVQLPNHFSNRYYNRLVRSLLECDEDTVSTIRDSLMEKIGPNMASLFHIL
QTDHCAQTHPRADFNRRRTNEPQKLKVLLRNLRGEEDSPSHIKRTSHESAASDYKDDDDK
which exhibits both hydrophilic (second shaded region, bolded residues) and hydrophobic (first shaded region, underlined residues) regions, wherein the hydrophilic region is at least 60% Asp, Glu, Lys, or Arg (11/18 residues*100 = 61.1%), and the hydrophobic region is at least 35% Tyr, Phe, Leu, or Val (5/10 residues*100=50%).
Regarding claims 20 and 22, the composition can be administered using any means known in the art; nonlimiting examples include topical, subconjunctival, sub-Tenon's, intravitreal, subretinal, or injection into the anterior chamber of the eye of a subject. Other modes of administration include systemic administration, including intravenous administration as well as oral administration. In a specific embodiment, the composition is administered intravitreally ([0014]).
Regarding claim 24, Rosa teaches a method of treating cataracts; as evidenced by Moreau, βD-crystallin and γD-crystallin are major components of the lens, thus making them prime candidates for cataract treatment.
Regarding claim 25, Rosa teach kits of the invention that come with instructions for use ([0020]).
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(s) 1-3, 8, 12, 17, 20, and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Rosa et al. (US20130143814A1, published 6/6/2013, cited on IDS filed 8/8/2024), as evidenced by Moreau et al. (Protein misfolding and aggregation in cataract disease and prospects for prevention. Trends Mol Med. 2012 May;18(5):273-82.), in view of Yang et al. (AU 2016271635 B2, published 11/4/2021).
The teachings of Rosa have been set forth above. Rosa does not teach the method of claim 1 wherein the polypeptide is fused with a cell-penetrating peptide.
Yang teaches compositions and methods for promoting the degradation of misfolded proteins and protein aggregates as well as methods of treatment thereof (Abstract). Yang teaches the composition can comprise one or more TRIM proteins, which may further comprise a cell penetrating peptide to allow for entry of the isolated peptide into a cell (Pg 4, lines 24-27).
Thus, regarding claim 12, it would be prima facie obvious to fuse a cell penetrating peptide to the peptide taught by Rosa. One skilled in the art would have a reasonable expectation of success and be motivated to do so in order to improve the entry of the peptide therapeutic into a target cell.
Regarding claim 17, Yang further teaches that peptides of the invention may be modified by introduction of tags such as His tags (Pg 81, lines 5-7).
Claim(s) 1-3, 8, 15-16, 20, and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Rosa et al. (US20130143814A1, published 6/6/2013, cited on IDS filed 8/8/2024), as evidenced by Moreau et al. (Protein misfolding and aggregation in cataract disease and prospects for prevention. Trends Mol Med. 2012 May;18(5):273-82.), in view of Ying et al. (US 20130023024 A1, published 1/24/2013).
The teachings of Rosa have been set forth above. Rosa does not teach the polypeptide wherein it is further fused with a linker.
Ying teaches conjugates provided for cell processing comprising a magnetic particle and a surface modifier having specific affinity to a target cell that are linked through a cleavable peptide bond (Abstract).
Regarding claim 15, it would be prima facie obvious to further attach a linker to the peptide taught by Rosa. One skilled in the art would have a reasonable expectation of success and be motivated to do so in order to be able to attach other biological moieties to the polypeptide.
Regarding claim 16, Ying teaches the linker Leu-Val-Pro-Arg-Gly-Ser, which is equivalent to the instant SEQ ID NO: 28 ([0007, 0045]).
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 1-11, 20, and 22-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 11-15 of U.S. Patent No. 11,970,517 B2 (US ‘517). Although the claims at issue are not identical, they are not patentably distinct from each other because practicing the instant method claims anticipates the claims of US ‘517.
Claims 1-11, 20, and 22-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 12,435,109 B2 (US ‘109). Although the claims at issue are not identical, they are not patentably distinct from each other because practicing the instant method claims anticipates the claims of US ‘109.
Claims 1-11, 15-17, 20, and 22-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 19/143,880 (‘880 reference application; claim set filed 6/26/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because practicing the instant method claims anticipates the claims of copending Application No. ‘880.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sara Konopelski Snavely whose telephone number is (571)272-1841. The examiner can normally be reached Monday - Friday 9-6pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa L Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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