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 .
DETAILED ACTION
Claims 16-20 are newly added. Claims 1-20 are pending and under examination.
Claim Objections
Claims 1, 5, 6, 10, 11, and 12-15 are objected to because of the following informalities: the claims contain grammatical errors and convoluted language.
Claims 1 and 12-15 further recite the acronym, CRALBP, but do not define what it stands for. The claims should be amended to recite the full protein name. The claims also recite: “able of forming a disulfide bond” and should be amended to recite “capable of forming a disulfide bond”.
Claim 5 contains an extra space, “monomeric complex” in line 2.
Claim 6 recites “a average diameter” and should be amended to recite “an average diameter”.
Claim 10 may be amended to:
The composition of claim 1, wherein said wild-type CRALBP protein is the human CRALBP protein of SEQ ID NO:3, and said mutein comprises one, , or three pairs of amino acid mutations to
:
s of amino acids 212
s of amino acids 217
s of amino acids 220
:
a. a first pair of amino acid mutations to to are mutations of amino acids 220 are mutations of amino acids 224
b. a first pair of amino acid mutations to to are mutations of amino acids 212 are mutations of amino acids 224
c. a first pair of amino acid mutations by cysteines and a second pair of amino acid mutations to are mutations of amino acids 212 are mutations of amino acids 217
to :
(x) a first pair of amino acid mutations to to to are mutations of amino acids 212 are mutations of amino acids 220 are mutations of amino acids 224
Claim 11 recites incomplete Markush language: “an amino acid sequence selected from group consisting of” should be amended to “the amino acid sequence selected from the group consisting of”.
Claim 14 may be amended to:
A method of preparing the complex of claim 1, comprising the steps of:
adding at a concentration of 1 µM to 5 mM to
adding at a concentration of 5µM to 500 mM to a -soluble solvent;
generating a solution III by combining to :molar[[)]], and wherein the volume of said water soluble solvent in
allowing said CRALBP mutant protein and said cognate ligand of CRALBP to assemble into a complex;
separating saidand
optionally purifying said .
Appropriate correction is required.
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 1-20 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.
Claims 1 and 12-15 recite CRALBP mutant proteins comprising amino acid mutations compared to a wild-type CRALBP protein, but the claims do not the SEQ ID NO corresponding to the sequence of the wild type protein as reference. The claims also recite: at least one pair of amino acid mutations by cysteines. It is unclear if the claim limitation means that amino acids are to be mutated or substituted to cysteine, or amino acid residues that are adjacent to or in the vicinity of cysteine residues in a primary amino acid sequence are to be mutated by insertion, deletion, or substitution with single or multiple residues. One of ordinary skill would not know what mutations are required by the claims.
Claims 2-11 and 16-20 are also rejected as they depend from claim 1.
Claims 2, 3, 4, 10, and 17 also recite: amino acid mutations by cysteines. It is unclear if the claim means that amino acids are to be mutated or substituted to cysteines, or if the claim means that amino acid residues that are adjacent to or in the vicinity of cysteine residues in a primary amino acid sequence are to be mutated by insertion, deletion, or substitution with single or multiple residues. One of ordinary skill would not know what mutations are required by the claims.
Claim 6 recites: an average diameter of about 24 to 33 nm. The term “about” is a term of approximation which renders the claim indefinite. The range that is encompassed by the term “about” is not defined by the claim, and the specification does not provide the upper and lower limits of the range encompassed by the term “about”. One of ordinary skill in the art would not be reasonably be apprised of the scope of the invention. It is therefore unclear what diameter is within approximation as required by the claim.
Regarding claim 11, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP §2173.05(d). A broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 11 recites the broad recitation “an amino acid sequence selected from group consisting of SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21 and SEQ ID NO:23”, and the claim also recites “an amino acid sequence selected from SEQ ID NO:9 and SESQ ID NO:21” and “the amino acid sequence of SEQ ID NO:9”, which are the narrower statement of the limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 14 and 15 recite: wherein the concentration of said cognate ligand of SEC14-like protein. It is unclear if the claim means that another cognate ligand of a different protein, i.e. SEC14, is to be bound to the CRALBP mutant. One of ordinary skill in the art would not know what ligand is required by the claims.
Claim 14 recites the limitation "the solvent" in step . There is insufficient antecedent basis for this limitation in the claim.
Claim 14 also recites (molar/molar) and (vol/vol). It is unclear if the terms in parentheses are required, or optional and thus not required, limitations of the instant claim.
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 1-20 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.
Claims 1-11 and 15-20 encompass the limitations of a composition comprising a complex, wherein said complex comprises: a) cellular retinaldehyde binding protein (CRALBP) mutant protein comprising at least one pair of amino acid mutations by cysteines as compared to wild type CRALBP, wherein each pair of cysteines is able to form a disulfide bond; and, b) a cognate ligand of CRALBP.
Claim 12 is drawn to a CRALBP mutant protein comprising at least one pair of amino acid mutations by cysteines as compared to wild type CRALBP, wherein each pair of cysteines is able to form a disulfide bond.
Claim 13 is drawn to a nucleic acid sequence encoding a CRALBP mutant protein comprising at least one pair of amino acid mutations by cysteines as compared to wild type CRALBP, wherein each pair of cysteines is able to form a disulfide bond.
Claim 14 is drawn to a method of preparing a composition comprising a complex, wherein said complex comprises: a) CRALBP mutant protein comprising at least one pair of amino acid mutations by cysteines as compared to wild type CRALBP, wherein each pair of cysteines is able to form a disulfide bond; and, b) a cognate ligand of CRALBP.
MPEP 2163.05 II states “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us].’”
The instant specification reduces to practice a CRALBP protein comprising the amino acid substitutions, A212C and T250C, shown in SEQ ID NO:9 (Example 5), and reduces to practice a complex comprising the CRALBP mutant shown in SEQ ID NO:9 bound to 9-cis-retinal (Figure 6), i.e., one protein species, one ligand species, and one complex species. The specification does not disclose the entire genus of claimed CRALBP mutant proteins or nucleic acids encoding said proteins, does not disclose the entire genus of claimed cognate ligands of CRALBP, and does not disclose the entire genus of claimed complexes comprising a CRALBP mutant and a cognate ligand of CRALBP. The instant specification does not disclose what structural properties are required for the protein to bind cognate ligands. Therefore, the disclosed species are not representative of the entire genus of claimed mutant proteins, ligands, and complexes.
Wu et al. (Mapping the Ligand Binding Pocket in the Cellular Retinaldehyde Binding Protein; THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 278, No. 14, p. 12390-12396, 2003) teaches 4 mutant CRALBP proteins that were able to bind 11-cis- and 9-cis-retinal, but with lower binding affinities, and teaches that Trp-265, Met-208, Met-222, Met-225, and Trp-244 are components of the CRALBP ligand binding cavity. However, Wu does not disclose all amino acid residues that are part of the CRALBP ligand binding cavity and does not disclose all residues that are required for ligand binding.
In sum, neither the instant specification, nor the prior art, discloses a structure-function relationship between conserved amino acid residues in the claimed protein structure and ligand binding activity. One of ordinary skill in the art cannot reasonably predict which residues of CRALBP may be modified to generate a functional carrier protein capable of binding to 11- or 9-cis-retinal. Based on the instant disclosure, those skilled in the art would not conclude that the applicant was in possession of all claimed variants.
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.
Claims 1, 8, 9, 15, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al., (Mapping the Ligand Binding Pocket in the Cellular Retinaldehyde Binding Protein; THE JOURNAL OF BIOLOGICAL CHEMISTRY. Vol. 278, No. 14, p. 12390-12396, 2003, cited in 11/16/2023 IDS).
Under BRI, any disulfide bond-containing CRALBP mutant bound to a cognate ligand of CRALBP meets the limitations of instant claim 1.
Regarding claim 1, Wu teaches CRALBP protein mutants comprising single substitutions M208A, W165F, and W244F, bound to 11-cis-retinal and 9-cis-retinal, which are considered cognate ligands of CRALBP (Figure 3). Wu does not teach that any cysteine residues are mutated or any disulfide bond formation, although Wu teaches the amino acid sequence of human rCRALBP (Figure 1) that contains cysteine residues, i.e. Cys36, Cys137, Cys180, and Cys198. Therefore, it is considered that the disulfide bonds are conserved, i.e., the mutant is capable of forming disulfide bonds.
Regarding claim 8, Wu does not teach that any cysteine residues are mutated or any disulfide bond formation, although Wu teaches the amino acid sequence of human rCRLBP (Figure 1) that contains cysteine residues, i.e. Cys36, Cys137, Cys180, and Cys198. Therefore, it is considered that the disulfide bonds are conserved, i.e., the mutant is capable of forming disulfide bonds.
Regarding claim 9, SEQ ID NO:3 is the human CRALBP and Wu teaches wild-type human CRALBP (Abstract) with 100% sequence identity to instant SEQ ID NO:3 (see alignment above and Wu Figure 1).
Regarding claim 15, Wu teaches CRALBP proteins comprising mutations M208A, W165F, and W244F, bound to 11-cis-retinal and 9-cis-retinal, which are considered cognate ligands of CRALBP (Figure 3). Wu does not teach that any cysteine residues are mutated or any disulfide bond formation, although Wu teaches the amino acid sequence of human rCRALBP (Figure 1) that contains cysteine residues, i.e. Cys36, Cys137, Cys180, and Cys198. Therefore, it is considered that the disulfide bonds are conserved, i.e., the mutant is capable of forming disulfide bonds.
The method of obtaining said composition is considered a product-by-process limitation and does not affect patentability. See MPEP 2113.I, which states: "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding claim 16, Wu teaches that the CRALBP proteins are bound to 11-cis-retinal and 9-cis-retinal (Figure 3), which are cis-retinoids.
Claims 5-7, 14, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al., (Mapping the Ligand Binding Pocket in the Cellular Retinaldehyde Binding Protein; THE JOURNAL OF BIOLOGICAL CHEMISTRY. Vol. 278, No. 14, p. 12390-12396, 2003) as applied to claim 1 above, and further in view of Stocker (WO2017/129555A1).
See discussion of Wu above, which is incorporated into this rejection as well.
Wu does not teach whether the CRALBP-ligand complexes are monomeric or oligomeric, and does not teach the method of preparing a CRALBP-ligand complex as recited in instant claim 14.
However, regarding claim 5, Stocker teaches cognate ligand-complexes comprising monomeric CRALBP-9-cis-reinal nanospheres (p. 9, lines 6-7). Stocker teaches that “nanosphere” refers to a composition formed by a number of SEC14-like proteins and an equal number of cognate ligands of said SEC14-like proteins (p. 9, lines 29-31).
Regarding claim 6, Stocker teaches CRALBP-11-cis-retinal oligomeric complexes (Example 10). Stocker teaches CRALBP-11-cis-retinal nanospheres in a size range between 9 and 48 nm (p. 9, line 5). The method of determining average diameter is considered a product-by-process claim and does not affect patentability.
Regarding claim 7, Stocker teaches mixtures comprising monomeric and homo-oligomeric complexes of CRALBP-9-cis--retinal (p. 43, Example 9).
Regarding claim 14, Stocker teaches that “nanosphere” refers to a composition formed by a number of SEC14-like proteins and an equal number of cognate ligands of said SEC14-like proteins (p. 9, lines 29-31). Stocker teaches CRALBP is a SEC14-like protein (p. 14, lines 31-32). Stocker teaches a method of producing a nanosphere comprising a human SEC14-like protein and a cognate ligand of said SEC14-like protein, wherein said method comprises:
a) providing said SEC14-like protein in an aqueous solution I, wherein the concentration of said SEC14-like protein in solution I is 1 µM to 5 mM, and wherein the pH of said solution I is 6 to 9
(b) providing said cognate ligand of SEC14-like protein in a solution II, wherein
the concentration of said cognate ligand of SEC14-like protein in said solution I is 5 μM to 500 mM, and wherein the solvent of said solution II is a water-soluble solvent;
(c) generating a solution III by combining said solution I and said solution II,
wherein the ratio of the concentration of said SEC14-like protein and the concentration of said cognate ligand of said SEC14-like protein in said solution III is between 4: 1 to 1 :4 (molar/molar), and wherein the volume of said water soluble solvent in said solution III is between 0.5-8% (vol/vol);
(d) allowing said SEC14-like protein and said cognate ligand of said SEC14-like protein to assemble into a nanosphere, i.e., a complex;
(e) separating said nanosphere from said solution III; and
(f) optionally purifying said nanosphere, i.e., the protein-ligand complex (p. 51, Claim 10).
Regarding claim 18, Stocker teaches CRALBP-9-cis-retinal nanospheres with masses of up to 1700 kDA (p. 9, lines 6-14).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to use the method of preparing monomeric and oligomeric nanosphere complexes as taught by Stocker, comprising the CRALBP mutant bound to 9- or 11-cis-retinal, as taught by Wu. One of ordinary skill in the art would have been motivated to do so because Stocker teaches that nanosphere complexes comprising SEC14-like proteins such as CRALPB (p. 14, lines 31-32) may be used to treat diseases (p. 7, para. 1). One of ordinary skill in the art would have had a reasonable expectation of success because Wu and Stocker are in the same field of endeavor of CRALBP-ligand complex studies.
Examiner’s Comment
There are no prior art references that teach a mutant of SEQ ID NO:3, comprising amino acid substitutions to cysteines at residues 212 and 250, at residues 217 and 253, at residues 220 and 254, or at residues 224 and 257.
There are no prior art references that teach the full-length amino acid sequence of SEQ ID NOs: 9, 11, 13, 15, 17, 19, 21, and 23.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657