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 2, 4, and 9 are canceled. Claims 21-23 are new. Claims 1, 3, 5-8, and 10-23 are pending and under consideration in this action.
Claim Objections
Claims 1 and 12-15 are objected to because of the following informalities: the claims contain grammatical errors and convoluted language.
Claim 1 and claims 12-13 respectively recite “selected from” in line 9 and in line 7, which should be replaced with “selected from:” because a colon should be used to introduce the list of four mutation pairs.
Claims 14 and 15 recites: i., ii., iii., iv., v. and vi., which should be replaced with (i), (ii), (iv), (v) and (vi) respectively because MPEP 608.01(m) states that periods may not be used elsewhere in the claims except for abbreviations.
Claim 15 can be amended to recite “solution III; and” in line 29 (second to last line). Claim 14 was previously objected to for not reciting “and” between steps v. and vi. See the non-final action mailed 01/15/2026 p. 6 line 2. Since claim 15 recites identical steps compared to claim 14, claim 15 should be amended to recite “and” in line 29 for consistency.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 5-8, and 10-23 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, 3, 5-8, 10-11 and 15-23 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 to cysteines as compared to wild type CRALBP, wherein each pair of cysteines form a disulfide bond; b) a cognate ligand of CRALBP.
Claim 12 is drawn to a CRALBP mutant protein comprising at least one pair of amino acid mutations to cysteines as compared to wild type CRALBP, wherein each pair of cysteines 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 to cysteines as compared to wild type CRALBP, wherein each pair of cysteines 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 to cysteines as compared to wild type CRALBP, wherein each pair of cysteines form a disulfide bond; 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.
Response to Arguments
Applicant's arguments filed 04/14/2026 have been fully considered but they are not persuasive.
Rejection of claims 1, 3, 5-8, and 10-23 under 35 U.S.C. 112(a)
Applicant argues that independent claims 1, 12, 13 and 15 were amended to recite “wherein said pair of amino acid mutations is selected from (1) mutations of amino acids 212 and 250 of SEQ ID NO:3, (2) mutations of amino acids 217 and 253 of SEQ ID NO:3, (3) mutations of amino acids 220 and 254 of SEQ ID NO:3, or (4) mutations of amino acids 224 and 257 of SEQ ID NO:3”. Support for the amendment is found throughout the specification and claims as originally filed. See the remarks p. 11 para. 3. For these reasons, Applicant asserts that the rejection under 35 U.S.C. 112(a) should be withdrawn. See the remarks p. 11 para. 4.
This argument is not persuasive because the amendment is insufficient to overcome the rejection. Independent claims 1, 12, 13 and 15 do not limit the structure of required CRALBP mutant protein as a whole. The independent claims only require the CRALBP mutant protein to have one of the recited mutation pairs relative to SEQ ID NO: 3, which limits two residues out of the CRALBP mutant protein as a whole. As such, the claims still encompass a variety of structurally diverse CRALBP mutant proteins. The instant specification reduces to practice one example of a complex between SEQ ID NO: 9 and 9-cis-retinal. See figure 6 and example 5. SEQ ID NO: 9 is 99.4% identical to instant SEQ ID NO: 3. The only difference between the two sequences is that SEQ ID NO:9 has the A212C and T250C mutation pair relative to SEQ ID NO:3. Therefore, the specification indicates that the A212C and T250C mutations may be required for the 9-cis-retinal ligand binding function. Claims 1, 3, 5-8, 10-18, and 22-23 do not require the A212C and T250C mutations. Claim 19 requires the CRALBP mutant protein to be selected from SEQ ID NO:9 and SEQ ID NO: 21, which both include the A212C and T250C mutations. Claim 20 and 21 limits the CRALBP mutant protein to SEQ ID NO: 9. However, claims 19-21 do not limit the ligand component of the complex to the 9-cis-retinal ligand reduced to practice in the specification. Therefore, the claims encompass a genus of CRALBP mutant and ligand complex combinations.
In order to substantially limit the structure of the CRALBP mutant as a whole, and consequently limit the genus of complexes, the following amendment is suggested:
A composition comprising a complexcomprising:
(a) a cellular retinal binding protein (CRALBP) mutant comprising the sequence of a , SEQ ID NO:3, except for A212C and T250C, wherein
(b) a cognate ligand of CRALBP.
3. The composition of claim 1, wherein said CRALBP mutant further comprises one, two, or three selected from: (1) T217C and V253C, (2) L220C and V254C, and/or (3) V224C and F257C.
11. The composition of claim 1, wherein said CRALBP mutant
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, 3, 5-8, 10-11, and 14-23 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 15, as amended, are indefinite because there is no conjunction between (a) and (b) and consequently it is unclear whether the claimed complex requires the limitations recited in (a) and (b), the limitations recited in (a) or (b), or whether the claim is incomplete. To obviate this rejection “SEQ ID NO:3; (b) a cognate ligand of CRALBP” (claim 1 lines 13-14, and claim 15 lines 12-13) can be amended to recite “SEQ ID NO:3; and (b) a cognate ligand of CRALBP” so that the claimed complexes clearly require the limitations recited in (a) and (b).
Claims 3, 5-8, 10-11, and 14, and 16-23 depend from claim 1 and are rejected for the reason set forth above.
Response to Arguments
Applicant's arguments filed 04/14/2026 have been fully considered but they do not apply to the new grounds of rejection set forth above.
Claim Rejections - 35 USC § 112(d)
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.
Claim 3 is 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.
Claim 3 fails to further limit claim 1 from which it depends. Claim 1 requires said pair of amino acid mutations to be selected from (1) mutations of amino acids 212 and 250 of SEQ ID NO:3, (2) mutations of amino acids 217 and 253 of SEQ ID NO:3, (3) mutations of amino acids 220 and 254 of SEQ ID NO:3, or (4) mutations of amino acids of 224 and 257 of SEQ ID NO:3. Therefore, claim 1 requires one mutation pair selected from (1)-(4). Claim 3 recites said mutein comprises one, two, three or four pairs of said amino acid mutations to cysteines. Since claim 3 encompasses mutein embodiments with one mutation pair, claim 3 does not further limit claim 1. To obviate this rejection, claims 1 and 3 can be amended as set forth above.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form as suggested above, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657
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