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 .
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Status of Application, Amendments and/or Claims
The amendment, filed 12 April 2023, has been entered in full. Claims 13 and 14 are canceled. Claims 7 and 10 are amended. New claims 15-19 are added. Claims 1-12, 15-19 are under examination.
Foreign Priority
Acknowledgment is made of Applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d). The certified copy KR 10-2020-0132203 has been placed of record in the file.
Because the document, upon which priority is claimed, is not in English it fails to provide adequate support. Therefore, the filing date of October 13, 2021 will be used for purposes of applying prior art. This date is the filing date of document 371 PCT/KR2021/014103.
Should Applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 5/26/23 and 11/4/25) were received and comply with the provisions of 37 CFR $1.97, 1.98 and MPEP § 609. They have been placed in the application file and the information referred to therein has been considered as to the merits.
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).
Claims 2, 4 and 6 recite sequences which are not identified by a SEQ ID NO:
In the specification, paragraphs 35, 38, 41, 48, 63, 64 and 196 recite sequences which are not identified by a SEQ ID NO:
The entire specification should be checked for sequences which are not identified by a SEQ ID NO:, 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.
Claim Objections
Claims 1, 3, 7 and 10 are objected to because of the following informalities
Claims 1 and 3 are objected to because on line 1, after the phrase “testosterone,” the phrase “wherein said polypeptide comprises” should be inserted.
Claim 7 is objected to because on line 1, the word “a” (in “a polypeptide”) should be amended to recite “the”.
Claim 10 is objected to because on line 2, “i)” should be deleted as there is only one element recited in the claim. Appropriate correction is required.
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 6, 10-12, 15-17 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 6 is indefinite because of the recitation, “The polypeptide of claim 1, wherein the polypeptide comprises all of the underlined amino acid residues in the following amino acid sequence…”
The claim is indefinite because it is unclear if the polypeptide also comprises the amino acid residues that are NOT underlined in the amino acid sequence.
The claim is also indefinite because it is unclear how claim 6 further limits claim 1. Claim 1 recites 94% sequence homology. SEQ ID NO:1 has 58 amino acid residues, meaning about 3 amino acid residues can be changed (6% x 58 = 3.48).
If the sequence in claim 6 is only required to comprise the underlined amino acid residues (14 amino acid residues), this means the sequence can have 44 amino acid changes. A sequence with 44 amino acid changes would not further limit a claim reciting 94% sequence homology to a 58 amino acid sequence polypeptide. The metes and bounds of claim 6 cannot be determined.
It is noted that if Applicant intends claim 6 to encompass the entirety of SEQ ID NO: 1 (with no amino acid changes), claim 6 could be amended to simply recite, “The polypeptide of claim 1, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 1”.
Claims 10, 12, 15, 17 are indefinite because of the recitation “A nucleic acid molecule” and “A host cell”, respectively.
The claims are indefinite because it is not clear if the claims encompass gene therapy and human host (or transgenic animals).
Amending the claims to recite, “An isolated nucleic acid molecule..” and “An isolated host cell..”, would be remedial. Claims 11 and 16 are included in this rejection insofar as they depend from claims 10 and 15, respectively and do not resolve the issue discussed above.
Claim 15 is indefinite because of the recitation, “A nucleic acid molecule comprising a nucleotide sequence encoding the complex of claim 7”.
It is unclear if the nucleotide sequence encodes the entire complex of claim 7 (i.e. at least 94% sequence homology to SEQ ID NO:1 and at least one angiogenic polypeptide) OR if the nucleotide sequence only encodes the polypeptide that specifically binds to testosterone (i.e. at least 94% sequence homology to SEQ ID NO:1).
In addition, there is no sequence recited for the “at least one angiogenic polypeptide” and thus it is unclear what nucleotide sequence would be encoding the angiogenic polypeptide.
Lastly, it is unclear if the nucleotide sequence encoding the complex are two separate nucleotide sequences of the complex or a fusion protein encoding the entire complex. The metes and bounds of claim 15 cannot be determined. Claims 16 and 17 are included in this rejection insofar as they depend from claim 15 and do not resolve the issue discussed above.
Claim Rejections - 35 USC § 112
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 1-12, 15-19 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 claims lack written description because there is no disclosure of a correlation between the structure of a polypeptide and the biological function of binding testosterone and treating hair loss, beyond the polypeptides disclosed in the examples in the specification.
The claims lack written description because there is no disclosure of a correlation between the structure of an angiogenic polypeptide and the biological function of angiogenesis, beyond the angiogenic polypeptide disclosed in the examples in the specification.
The specification has written description for:
A polypeptide that specifically binds to testosterone comprising the amino acid sequence of SEQ ID NO:1 wherein the glutamine residue (Q) at position 11, the serine residue (S) at position 17 or the threonine residue (T) at position 25 of SEQ ID NO:1 is replaced with an alanine residue (A) (see claim 4).
A polypeptide that specifically binds to testosterone comprising the amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs:1, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 20, 21 and 22 (see claim 5).
wherein said angiogenic polypeptide is osteopontin or a fragment thereof (see claims 8 and 9).
But lacks written description for:
A polypeptide that specifically binds to testosterone, comprising an amino acid sequence having at least 94% sequence homology with the following amino acid sequence of SEQ ID NO:1 (claim 1)
The polypeptide of claim 1, wherein at least one amino acid residue selected from the glutamine residue (Q) at position the 11, the serine residue (S) at position 17, and the threonine residue (T) at position 25 of the following amino acid sequence is independently replaced with any amino acid residue: VDNKFNKEMVQAMREISYLPNLNHTQIRAFIWVLFDDPSQSANLLAEAKKLNDAQAPK (claim 2)
The polypeptide of claim 1 that specifically binds to testosterone comprising an amino acid sequence having at least 98% sequence homology with the amino acid sequence of SEQ ID NO:1 (claim 3).
The polypeptide of claim 1, wherein the polypeptide comprises all of the underlined amino acid residues in the following amino acid sequence: VDNKFNKEMVQAMREISYLPNLNHTQIRAFIWVLFDDPSQSANLLAEAKKLNDAQAPK (claim 6).
A complex comprising a polypeptide that specifically binds to testosterone of claim 1 and at least one angiogenic polypeptide (claim 7) AND claims 10-12 and 15-19.
MPEP§ 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (show a structure is correlated with the function) OR through a sufficient description of a representative number of species (show a representative number of species that have the function. There must be enough species that are representative of the full breadth of the genus).
Regarding structure-function correlation: The problem of predicting protein structure and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex. It is in no way predictable that randomly selected changes in the disclosed sequence would afford a protein having activity comparable to the one disclosed.
For sequences having one or two substitutions, for example, the artisan would reasonably expect that many of the possible variants would retain functional properties comparable to those of the unmodified protein, and it would require only routine manipulations to make and test a reasonably representative sampling of the possible variants. However, as the number of modified sites increases, the number of possible variants, and hence the degree of experimentation required, increases exponentially. Additionally, as plural substitutions are introduced, their interactions with each other and their effects on the structure and function of the protein become progressively less predictable.
Even if the instant specification outlined art-recognized procedures for producing and screening for active muteins, this is not adequate guidance as to the nature of active derivatives that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation. The ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active; conformation is dependent upon surrounding residues. Substitution of non-essential residues can often destroy activity
For example, Fenton et al. state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at non-conserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs (see entire reference)(Rheostat positions: A new classification of protein positions relevant to pharmacogenomics Medicinal Chemistry Research 29:1133-1146; 2020).
Bhattacharya et al. state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18)(Impact of genetic variation on three-dimensional structure and function of proteins PLoS ONE 12(3): e0171355; 2017). See also Tokuriki et al. (Stability effects of mutations and protein evolvability, Current Opinion in Structural Biology, 19:596-604, 2009).
In addition, when multiple mutations are introduced, there is even less predictability. As the number of modified sites increases, the number of possible variants, and hence the degree of experimentation required, increases exponentially. As plural substitutions are introduced, their interactions with each other and their effects on the structure and function of the protein become progressively less predictable. For evidence thereof, see Guo et al., who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2)(Guo et al. Protein tolerance to random amino acid change. PNAS USA 101(25):9205-10; 2004).
The state of the art evidences the unpredictability of the effects of mutation on protein structure and function.
Regarding a representative number of species: The instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. There must be enough species that are representative of the full breadth of the genus. A "representative number of species" means that the species, which is adequately described, is representative of the entire genus. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case: Claim 1 is drawn to a polypeptide having at least 94% sequence homology to SEQ ID NO:1, which encompasses up to 6% of amino acid residue changes. The amino acid residue changes include additions, deletions and/or substitutions in SEQ ID NO:1. SEQ ID NO:1 has 58 amino acid residues, meaning about 3 amino acid residues can be changed (0.6 x 58 = 3.48).
Claim 2 is drawn to SEQ ID NO:1 wherein at least one amino acid residue at position 11, 17 and/or 25 is replaced with any amino acid. There are 20 amino acids. Therefore, all three positions have a choice of 19 other amino acid residues.
Claim 3 is drawn to claim 1 that specifically binds to testosterone comprising an amino acid sequence having at least 98% sequence homology with the amino acid sequence of SEQ ID NO:1, which encompasses up to 2% of amino acid residue changes at any position.
Claim 6 is drawn to SEQ ID NO:1 wherein SEQ ID NO:1 is only required to comprise certain amino acid residues (underlined amino acid residues).
Claim 7 is drawn to any angiogenic polypeptide.
The specification teaches the following:
A. Figure 1 teaches that only certain amino acid positions in SEQ ID NO:1 can have a substitution with an alanine residue and still bind testosterone. These positions are position 11 or position 17 or position 25.
B. Table 1 from the specification teaches single amino acid substitutions at position 11 or position 17 or position 25 in SEQ ID NO:1.
C. Figure 2 teaches single amino acid substitutions at position 25 in SEQ ID NO:1. Substitutions with amino acid residues aspartic acid, proline, isoleucine, leucine or phenylalanine at position 25 of SEQ ID NO:1 have very low to no binding to testosterone conjugated bovine serum albumin (T17-G-BSA).
D. Figure 4 teaches different binding specificity among the single amino acid substitutions at position 25 mutants to testosterone-conjugated BSA (T3-CMO-BSA and T17-G-BSA).
E. Figure 7 teaches the results of SEQ ID NO:1 (T26) and SEQ ID NO:1 linked to a fragment of osteopontin protein (T26-INS001) binding to testosterone-conjugated BSA (T3-CMO-BSA and T17-G-BSA).
F. Figure 9 teaches the ability of SEQ ID NO:1 (T26) and SEQ ID NO:1 linked to a fragment of osteopontin protein (T26-INS001) to stimulate hair growth on a mouse model wherein hair on the backs of mice were removed using a depilator.
The specification fails to teach a polypeptide having at least 94% sequence homology to SEQ ID NO:1 wherein 6% of amino acid residue additions, deletions and/or substitutions can occur anywhere in the sequence of SEQ ID NO:1 with any amino acid residue, while still maintaining the biological function of binding testosterone and treating hair loss.
The specification fails to teach a polypeptide wherein at least one amino acid residue at position 11, 17 and/or 25 is replaced with any amino acid reside in SEQ ID NO:1, while still maintaining the biological function of binding testosterone and treating hair loss.
The specification fails to teach a polypeptide having at least 98% sequence homology to SEQ ID NO:1 wherein 2% of amino acid residue additions, deletions and/or substitutions can occur anywhere in the sequence of SEQ ID NO:1 with any amino acid residue, while still maintaining the biological function of binding testosterone and treating hair loss.
The specification fails to teach a polypeptide wherein only certain amino acid residues (underlined amino acid residues) are required in SEQ ID NO:1, while still maintaining the biological function of binding testosterone and treating hair loss..
In addition, the specification states that the angiogenic polypeptide included in the complex of the present disclosure may be any other polypeptide having a suitable angiogenic function. The specification only teaches osteopontin. The specification teaches a complex in which the T26 affibody and the fragment of osteopontin protein (SVYGLR) were linked by a peptide linker (GGGG) and named it T26-INS001 (para 0157). In this particular instance, the claim depends on a recited property (angiogenic function), where the claim covers every conceivable structure for achieving the stated property, while the instant specification discloses one species (osteopontin).
Thus, the specification teaches a polypeptide comprising SEQ ID NO:1 with the biological function of binding testosterone and treating hair loss.
The specification teaches a polypeptide comprising SEQ ID NO:1 with a single substitution with an alanine reside at position 11 OR position 17 OR position 25, with the biological function of binding testosterone.
The specification teaches a polypeptide comprising SEQ ID NO:1 with a single substitution with certain amino acid residues at position 25, with the biological function of binding testosterone.
The specification teaches an angiogenic polypeptide that is osteopontin.
However, the disclosed species taught in the instant specification are not representative of the claimed genus, which encompasses variant sequences having the required function encompassed by the claims. There is substantial variation within the genus and the instant specification fails to describe a sufficient variety of species to reflect the variation within the genus. There must be enough species that are representative of the full breadth of the genus.
There is no information regarding what structural features would likely be associated with such function. The specification does not describe the structure for substitution variants, deletion variants and/or insertion variants with the biological function.
There is no art-recognized correlation between any structure and the biological function of binding testosterone and treating hair loss, based on which those of ordinary skill in the art could predict which part of the structure can vary without losing activity, particularly in view of the therapeutic intentions. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which of those molecules have the claimed activity.
The skilled artisan cannot envision the detailed chemical structure of the encompassed claimed molecules (if any) which have the activity without further testing, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification.
The courts have specifically stated that the skilled artisan cannot envision the detailed chemical structure of an encompassed polypeptide until the structure is disclosed, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. §112, first paragraph.
Potential Allowable subject matter
Claim 4 would be allowed if rewritten in independent form. Claim 4 also needs to be amended to recite a SEQ ID NO:
Claim 5 would be allowed if rewritten in independent form or amended to depend from independent claim 4.
CLOSEST PRIOR ART
Volpato et al. (Reference submitted by Applicant; IN FIERI S.R.I. WO 2013/011431) teach a polypeptide that binds testosterone. Volpato et al. teach a topical composition for treating alopecia comprising anti-testosterone antibodies. Volpato et al. do not teach a polypeptide comprising SEQ ID Nos: 1, 5, 6, 7, 9, 10, 11, 12,13, 14, 16, 20, 21, and 22.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REGINA M DEBERRY whose telephone number is (571)272-0882. The examiner can normally be reached M-F 9:00-6:30 pm (alt Fri).
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/R.M.D/Examiner, Art Unit 1647 5/11/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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