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 1-20 are pending and under consideration in this action.
The instant claims are entitled to the effective filing date of 08/09/2021.
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.
Claim 2 is 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 2 recites "accumulating the CLP in a medium, wherein the fermentation broth is obtained and separating the host cell from the fermentation broth" in lines 3-4, which is indefinite because this limitation does not set forth which mode of operation is required for such accumulation. Claim 2 further recites "accumulating the CLP in the host cell" in line 5, which is indefinite as it does not set forth the required action, and the claim does not set forth the structural relation to the other required active steps of separating the host cell from the fermentation broth, or extracting the CLP from the host cell.
Response to Arguments
Applicant's arguments filed 05/20/2026 have been fully considered but they are not persuasive.
Rejection of claim 2 under 35 U.S.C. 112(b)
Applicant argues that claim 2 is suitably definite. Applicant asserts that one need not define the means for accumulating the CLP in a medium or in a host cell for the claim to be clear. Applicant argues that claim 2, feature (ii) does not refer to separating the host cell from the fermentation broth as this is the alternative feature (i). The phrase “extracting the CLP from the host cell in feature (ii) is sufficiently clear without further amendment. See the remarks the paragraph spanning p. 7-8.
This argument is not persuasive because the active method step(s) required in claim 2 are unclear. Claim 2 recites “(i) accumulating the CLP in a medium, wherein the fermentation broth is obtained and separating the host cell from the fermentation broth” in lines 2-3. The recitation “accumulating the CLP in a medium” does not require an action nor does the recitation limit the medium to the fermentation broth. The recitation is followed by a wherein clause, i.e. “wherein the fermentation broth is obtained and separating the host cell from the fermentation broth”. However, there is no congruency between the recitation and the wherein clause because “a medium” is not equivalent “the fermentation broth”. Therefore, in one interpretation (i) requires three method steps: accumulating the CLP in any medium by any means, obtaining the fermentation broth and separating the host cell from the fermentation broth. Under an alternative interpretation (i) requires two method steps: obtaining the fermentation broth and separating the host cell from the fermentation broth, such that the CLP is accumulated in a medium. In both interpretations, it is unclear when the steps of claim 2(i) occur relative to steps a)-c) of claim 1. Claim 2 further recites “(ii) accumulating the CLP in the host cell and extracting the CLP from the host cell”. The recitation “accumulating the CLP in the host cell” is not an active method step. Therefore, the recitation reasonably limits the structure of the host cell to cells that do not secrete the CLP, such that the CLP can accumulate within the cell. As such, the recitation reasonably limits the host cell that is fermented in step a) of claim 1. However, the claim further recites “extracting the CLP from the host cell”, and it is unclear when the extraction step is required to be performed relative to steps a)-c) of claim 1.
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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ramshaw (US 2016/0046692) in view of Gopinath (European Biophysics Journal, 2014, 43(12), 643-652) with evidence from Frontier (Reagents & Solvents, 2023 University of Rochester).
Regarding claim 1, Ramshaw teaches a method for purifying triple-helical or collagen-like proteins recombinantly produced from a bacterial, yeast or plant host cell. See [0004]. In example 12, Ramshaw teaches cloning a DNA construct into E. coli for triple-helical protein expression. See paragraph [0160]. The term “triple helical protein” includes “collagen-like (CL) proteins”. See [0092]. Ramshaw teaches the DNA sequence of the bacterial collagen Scl2 from Streptococcus pyogenes. See [0080]. For expression, the E. coli host cells are grown in a medium, such as a defined medium. Ramshaw indicates that the defined medium is a liquid broth because the components are described per liter. See [0161]. Ramshaw teaches growing cells at 37˚C for 24 h, then incubating cells at 25˚C for 10 h, decreasing the temperature to 15˚C, and incubating for another 14h. After 24 h of incubation, the cells are harvested. See [0162]. Ramshaw teaches precipitating host cell materials from the triple-helical protein under acidic condition. See claim 20 of Ramshaw. For acidic precipitation, Ramshaw suggests that acetic acid can be used. Ramshaw discloses that the acidification step precipitates out contaminating host cell proteins whilst keeping the triple-helical protein in solution. See [0126].
Although Ramshaw does not explicitly teach folding of the CLP by incubating a fermentation broth for at least 1 h at not more than 25˚C, Ramshaw teaches incubating cells at 25˚C for 10 h and at 15˚C for 14 h after growing the cells at 37˚C for 24 hours, which meets the requirement as recited in the instant claim 1 for folding of the CLP. Thus, it would have been obvious to one or ordinary skill in the art that Ramshaw's incubation necessarily results in folding of the CLP.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to incubate host cells at 25˚C for 10 h, decrease the temperature to 15˚C, and incubate for another 14h, as taught by Ramshaw, because Ramshaw teaches cold shock bacterial expression systems (see [0069]), and in example 12 Ramshaw demonstrates using pColdIII (see [0161]). There would have been a reasonable expectation of success, because Ramshaw suggests that the recombinantly expressed triple-helical proteins remain soluble throughout precipitation (see claim 1 of Ramshaw).
Ramshaw does not teach c) purifying the CLP by solvent precipitation in which the CLP is precipitated.
Gopinath teaches that collagen precipitates in high concentration of ethanol ≥60% v/v. See the first sentence of the conclusion section. Gopinath teaches a stock solution of collagen (4mg/ml) prepared in acetic acid solution. For different concentrations of ethanol, the collagen stock solution is diluted by adding appropriate volumes of acetic acid and ethanol. See the paragraph spanning ps. 644-645. Gopinath teaches that the ethanol content, single shot or gradual exposure, to between 60% and 90% induces formation of a gel-like precipitate. See the sentence spanning ps. 645-646. Gopinath suggests that precipitation of the collagen in the presence of ethanol brings collagen molecules closer, possibly because of its dehydrating effect. See p. 648 right column first passage.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute Gopinath’s ethanol precipitation for Ramshaw’s acid precipitation. One of ordinary skill in the art would have been motivated to do so because Ramshaw suggests that the triple-helical protein can be converted to gelatin which can be useful for various application (see [0075]); and Gopinath teaches precipitating collagen in ethanol to form a gel-like precipitate (see the sentence spanning ps. 645-646). There would have been a reasonable expectation of success because Ramshaw suggests using acetic acid for acidic precipitation; and Gopinath demonstrates precipitating collagen in acetic acid and ethanol.
Regarding claim 2, Ramshaw teaches host cell cultures in which the triple-helical protein is secreted (i.e. accumulated) into the culture medium. Intact host cells can be removed or separated from the secreted-helical protein. See [0099]. Furthermore, Ramshaw teaches host cell cultures in which the triple-helical protein is retained (i.e. accumulated) within the host cell and released by rupture or extraction process. See [0100].
Regarding claim 3, Gopinath teaches that the ethanol content, single shot or gradual exposure, to between 60% and 90% induces formation of a gel-like precipitate. See the sentence spanning ps. 645-646. Thus, Gopinath teaches ethanol solvent concentrations of at least 5% as instantly required.
Regarding claim 4, Ramshaw teaches a precipitation step that is conducted at a temperature that is less than the melting temperature of the triple-helical protein. See claim 6 of Ramshaw. The melting temperature of the collagen-like domain of S. pyogenes (Scl2) at a neutral pH is 35.9˚C, and at an acidic pH is 25.7˚C. See table 1 in paragraph [0039].
Gopinath teaches preparing and incubating collagen at ~34˚C [for ethanol precipitation]. Gopinath teaches a low-temperature incubation in which samples are stored under refrigeration 5˚C [for ethanol precipitation]. See p. 645 first passage.
Therefore, Ramshaw and Gopinath teach solvent precipitations at a temperature of 37˚C or less, as instantly required.
Regarding claim 5, Ramshaw suggests that acetic acid (i.e. an organic solvent) can be used for acidic precipitation. See [0126].
Gopinath teaches precipitating collagen in ethanol (i.e. an organic solvent). See the first sentence of the conclusion section.
Therefore, Ramshaw and Gopinath teach organic solvents.
Regarding claims 6 and 14-15, Ramshaw teaches acidic precipitation with acetic acid. See [0126]. As evidenced by Frontier (p.1), acetic acid has a relative polarity of 0.648.
Gopinath teaches precipitating collagen in ethanol. See the first sentence of the conclusion section. As evidenced by Frontier (p.1), ethanol has a relative polarity of 0.654.
Therefore, Ramshaw and Gopinath both teach organic polar solvents with relative polarities less than 0.9 and less than 0.7.
Regarding claim 7, Gopinath teaches precipitating collagen in ethanol (i.e. an organic solvent). See the first sentence of the conclusion section.
Regarding claim 8, Ramshaw teaches freeze drying S. pyogenes collagen at 20˚C. See [0190]. Ramshaw teaches ultra filtration. See [0131]. Ramshaw teaches ion exchange chromatography. See [0049]. Ramshaw teaches inserting a thrombin/trypsin cleavage sequence between the N-terminal globular domain (V) and following the (Gly-Xaa-Yaa)n collagen-like domain [Scl2 from S. pyogenes]. See [0138]. Ramshaw teaches digesting host cell materials present in the precipitated host cell culture extract or homogenate by addition of a protease. See claim 1 of Ramshaw.
Regarding claim 9, Ramshaw teaches growing cells at 37˚C for 24 h, then incubating at 25˚C for 10 h, and 15˚C for another 14h. See [0162].
Ramshaw does not teach the folding of the CLP that occurs during the incubating step b) is performed with a CLP-concentration of at least 1 mg/ml.
Gopinath teaches preparing a stock solution of collagen with 4mg/ml in acetic acid solution, before precipitation with ethanol. See the paragraph spanning pages 644-645.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Ramshaw’s triple-helical CLP protein concentration during the incubation taught by Ramshaw based on Gopinath’s suggestion. One of ordinary skill in the art would have been motivated to do so because Ramshaw suggests applying a concentration technique (see [0030]), and Gopinath suggests a 4mg/ml concentration. There would have been a reasonable expectation of success because Gopinath demonstrates preparing collagen to concentrations of 4 mg/mL which is at least 1 mg/ml as instantly required.
Regarding claim 10, Ramshaw teaches SEQ ID NO: 2, which is the DNA sequence of a bacterial collagen Scl2 fragment from Streptococcus pyogenes. See [0080].
Regarding claim 11, Ramshaw teaches a method for the purification of a recombinantly expressed triple-helical protein contained within a non-mammalian host cell culture extract or homogenate, wherein the host cell is a bacterial, yeast or plant cell. See claims 1 and 4 of Ramshaw.
Regarding claim 12, Gopinath teaches that the ethanol content, single shot or gradual exposure, to between 60% and 90% induces formation of a gel-like precipitate. See the sentence spanning ps. 645-646. Thus, Gopinath teaches ethanol solvent concentrations of at least 15%.
Regarding claim 13, Ramshaw teaches that depending on the melting temperature (Tm) of the recombinant protein at the pH of the acidification solution the temperature at which the acidification occurs can vary between 4˚C and 30˚C, which overlaps with the instantly required 20˚C or less. See [0029].
Gopinath teaches a low-temperature incubation in which samples are stored under refrigeration 5˚C [for ethanol precipitation]. See p. 645 first passage.
Regarding claim 16, Ramshaw teaches freeze drying S. pyogenes collagen. See [0190].
Gopinath teaches lyophilizing (i.e. freeze drying) collagen. See p. 644 right column last full paragraph.
Regarding claim 17, Ramshaw teaches a digestion step using a protease, preferably an acid protease including pepsin. See [0043]. Non-acidic proteases may also be used in digestion, such as trypsin. See [0044].
Regarding claim 18, Ramshaw teaches growing cells at 37˚C for 24 h, then incubating cells at 15˚C, which is between 0˚C and 20˚C as instantly required. See [0162].
Regarding claim 19, Ramshaw teaches incubating cells at 25˚C for 10 h, and 15˚C for another 14h. See [0162]. Thus, Ramshaw teaches an incubation between 1h and 24h as instantly required.
Regarding claim 20, Ramshaw teaches growing cells at 37˚C for 24 h, then incubating at 25˚C for 10 h, and 15˚C for another 14h. See [0162]. Ramshaw teaches an intermediary separation step for separating the triple-helical protein from precipitated host cell materials. Such processes are crude separation or concentration techniques such as centrifugation, filtration, cross flow filtration or sedimentation. See [0030].
Ramshaw does not teach folding of the CLP with a concentration of at least 4 mg/ml.
Gopinath teaches preparing a stock solution of collagen with 4mg/ml in acetic acid solution, before precipitation with ethanol. See the paragraph spanning pages 644-645.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize the concentration of the triple-helical CLP protein of Ramshaw based on Gopinath’s suggestion. One of ordinary skill in the art would have been motivated to do so because Ramshaw suggests applying a concentration technique as an intermediary step; and Gopinath suggests a 4mg/ml collagen concentration. There would be a reasonable expectation of success because Gopinath demonstrates preparing collagen to concentrations of 4 mg/mL.
Response to Arguments
Applicant's arguments filed 05/20/2026 have been fully considered to the extent that they might apply to the new grounds of rejection set forth above, but they are unpersuasive.
Applicant argues that Ramshaw discloses acidic precipitation using acetic acid. In the claimed method the CLP is precipitated of solution. This distinguishes from the acidic fermentation of Ramshaw in which the triple helix protein remains in solution and undesired host cell proteins are precipitated (paras. [0035] and [0126] of Ramshaw). See the remarks p. 8 last full paragraph.
This argument is not persuasive because Ramshaw is not relied upon for teaching the claim element of amended claim 1 that requires “solvent precipitation in which the CLP is precipitated. Rather, Gopinath is relied upon for teaching that element.
Applicant argues that one would not combine Gopinath with Ramshaw since Gopinath is different in disclosing precipitating collagen from mammals, not collagen-like-protein from bacteria. One would not expect a likelihood of success in view of the unknown precipitation conditions of the collagen-liked protein relative to collagen. See the remarks p. 10 first passage.
This argument is not persuasive because MPEP 2141.01(a)(I) states that “[w]hen more than one prior art reference is used as the basis of an obviousness rejection, it is not required that the references be analogous art to each other”. See Sanofi-Aventis Deutschland GMbH v. Mylan Pharms. Inc., 66 F.4th 1373, 1380, 2023 USPQ2d 552 (Fed. Cir. 2023). In the instant case, Ramshaw and Gopinath are in the same field of endeavor compared to the instant invention. Ramshaw teaches that the term “collagen-like (CL)” refers to a polypeptide comprising Gly-X-Y triplets (see [0093]). Gopinath teaches collagen comprising Gly-X-Y triplet sequence (see p. 643 right column last passage). Considering the structural similarities between collagen-like protein and mammalian collagen, there would have been a reasonable expectation of success.
Applicant argues that one would not have used ethanol in higher concentration or the conditions in Gopinath that would cause collagen to precipitate out of solution and be denatured, since this is contrary to the disclosure of Ramshaw. See the remarks p. 10 first passage.
This argument is not persuasive because Gopinath suggests that “[t]he self-association of collagen at high ethanol content is probably the result of the dehydrating effect of ethanol, which removes loosely bound water while perhaps preserving the innermost layer of water that protects the triple helix” (p. 646 left column last paragraph). Thus, Gopinath suggests that the triple helical structure may be maintained.
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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12146175 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the narrow scope of patent claims 1-12 anticipates instant claims 1-20.
Patent claim 1 recites a method for producing a recombinant collagen-like protein (CLP), the method comprising:
a) fermenting at least one host cell, expressing a CLP with an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO:8 or SEQ ID NO:9, in a medium, wherein the amino acid sequence comprises a deletion of at least 38 amino acids at the N-terminus of the amino acid sequence of SEQ ID NO:1,
b) accumulating the CLP in the medium, wherein a fermentation broth is obtained,
c) separating the at least one host cell from the fermentation broth to obtain a supernatant,
d) incubating the supernatant of the fermentation broth of c) for at least 1 h at a temperature between 0° C. and 20° C. for folding of the CLP,
e) optionally purifying the CLP by at least one selected from the group consisting of: solvent precipitation, tangential flow filtration (TFF), ion exchange chromatography, and reversed-phase chromatography,
wherein said at least one host cell is at least one host cell selected from the group consisting of Pichia pastoris, Brevibacillus choshinensis, Corynebacterium glutamicum and Escherichia coli.
Patent claim 2 recites the method according to claim 1, wherein the amino acid sequence comprises a deletion of between 38 and 90 amino acids at the N-terminus of the amino acid sequence of SEQ ID NO:1.
Patent claim 3 recites the method according to claim 1, wherein the CLP is a collagen-like protein from Streptococcus pyogenes.
Patent claim 4 recites the method according to claim 1, wherein the folding of the CLP in d) is performed for a time between 1 h and 48 h.
Patent claim 5 recites the method according to claim 1, wherein the folding of the CLP in d) is performed with a concentration of the CLP of at least 1 mg/ml.
Patent claim 6 recites the method according to claim 1, wherein the amino acid sequence is 100% identical to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 or SEQ ID NO:9.
Patent claim 7 recites the method according to claim 1, wherein the amino acid sequence is 97% identical to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 or SEQ ID NO:9.
Patent claim 8 recites the method according to claim 1, wherein the amino acid sequence is 98% identical to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 or SEQ ID NO:9.
Patent claim 9 recites the method according to claim 1, wherein the amino acid sequence is 99% identical to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO: 4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 or SEQ ID NO:9.
Patent claim 10 recites the method according to claim 1, wherein the folding of the CLP in d) is performed for a time between 1 h and 24 h.
Patent claim 11 recites the method according to claim 1, wherein the folding of the CLP in d) is performed with a concentration of the CLP of at least 4 mg/ml.
Patent claim 12 recites the method according to claim 1, wherein said at least one host cell is Pichia pastoris.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 15-16 of copending Application No. 18/682,348 in view of Ramshaw (US 2016/0046692) and Gopinath (European Biophysics Journal, 2014, 43(12), 643-652) with evidence from Frontier (Reagents & Solvents, 2023 University of Rochester).
Copending claim 1 recites a polynucleotide encoding an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 1, wherein the polynucleotide is a replicable polynucleotide encoding a collagen-like protein, and wherein the amino acid sequence comprises a deletion of at least 38 amino acids at the N-terminus of the amino acid sequence of SEQ ID NO: 1.
Copending claim 5 recites the polynucleotide according to claim 1, wherein a nucleotide sequence is a replicable nucleotide sequence encoding the collagen-like protein from Streptococcus pyogenes.
Copending claim 6 recites a vector, comprising: the polynucleotide according to claim 1.
Copending claim 7 recites the polypeptide, comprising: an amino acid sequence encoded by the polynucleotide according to claim 1.
Copending claim 8 recites a microorganism, comprising: the polynucleotide according to claim 1.
Copending claim 9 recites the microorganism according to claim 8, wherein the microorganism is of the genus Pichia, Brevibacillus, Bacillus Escherichia or Corynebacterium.
Copending claim 11 recites the microorganism according to claim 8, wherein the microorganism has the capability of secreting a bacterial collagen-like protein.
Copending claim 12 recites the fermentative process for secreting a bacterial collagen-like protein in a host, comprising:
a) fermentation of the microorganism according to claim 8 in a medium,
b) accumulation of the bacterial collagen-like protein in the medium, wherein a fermentation broth is obtained.
Copending claim 16 recites the microorganism according to claim 8, wherein the microorganism is Pichia pastoris, Brevibacillus choshinensis or Corynebacterium glutamicum.
The copending claims lack: incubating a fermentation broth for at least 1 h at 25˚C or a lower temperature; and purifying the CLP by solvent precipitation in which the CLP is precipitated (relevant to instant claim 1); separating the host cell from the fermentation broth (relevant to instant claim 2); solvent precipitation at a solvent concentration of at least 15% (relevant to instant claims 3 and 12), at a temperature of 20 ˚C or less (relevant to instant claims 4 and 13) with an organic polar solvent with a relative polarity less than 0.7 (relevant to instant claims 5-6, and 14-15), an organic solvent selected from a group that includes ethanol (relevant to instant claim 7). The copending claims lack: a method further comprising drying at low temperature below 37 ˚C including freeze-drying, and/or additional ultrafiltration, solvent precipitation, TFF, or ion exchange chromatography, and/or incubating the CLP with a protease including trypsin and pepsin (relevant to instant claims 8 and 16-17); [incubating] CLP at a temperature between 0˚C and 20˚C, for a time between 1 and 24 h, and at a concentration of at least 4 mg/ml (relevant to instant claims 9 and 18-20).
However, Ramshaw incubating cells in a liquid defined medium (see [0161]) at 25˚C for 10 h, and 15˚C and incubating for another 14h. See [0162]. Ramshaw teaches an acid precipitation, where suitable acids include acetic acid. See [0126]. Gopinath teaches preparing a stock solution of collagen with 4mg/ml in acetic acid solution, before precipitation with ethanol (i.e. organic polar solvent). See the paragraph spanning pages 644-645. Gopinath teaches that the ethanol content, single shot or gradual exposure, to between 60% and 90% induces formation of a gel-like precipitate. See the sentence spanning ps. 645-646. Evidentiary reference Frontier discloses that ethanol has a relative polarity of 0.654. See page 1 of Frontier (relevant to instant claims 1, 3, 5-7, 9, 12, 14-15, 18-19). Ramshaw teaches removing intact host cells from the secreted-helical protein. See [0099] (relevant to instant claim 2). Gopinath teaches a low-temperature incubation in which samples are stored under refrigeration 5˚C [for ethanol precipitation]. See p. 645 first passage (relevant to instant claims 4 and 13). Gopinath teaches precipitating collagen in ethanol. See the abstract (relevant to instant claim 7). Ramshaw teaches freeze drying S. pyogenes collagen. See [0190]. Ramshaw teaches digesting using a protease, such as pepsin or trypsin. See [0043]-[0044] and claim 1 of Ramshaw (relevant to instant claims 8 and 16-17). Ramshaw teaches intermediary concentration techniques. See [0030].Gopinath teaches preparing a stock solution of collagen with 4mg/ml in acetic acid solution, before precipitation with ethanol. See the paragraph spanning pages 644-645 (relevant to instant claim 20).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply the incubation technique of Ramshaw and the ethanol solvent precipitation technique of Gopinath to the microorganism and collagen-like protein recited in the copending claims in order to produce a recombinant collagen-like protein.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 05/20/2026 have been fully considered, but they are not persuasive.
Double Patenting Rejection
Applicant argues that ‘175 patent discloses a different temperature than the claimed step of incubating fermentation broth from step a) for at least 1 h at 25˚C or a lower temperature such that the CLP is folded during this incubation. See the remarks p. 10 second to last paragraph. Therefore the nonstatutory obvious-type double patenting over the ‘175 patent is unsustainable. See the remarks p. 10 last full paragraph.
This argument is not persuasive because the narrow scope of the patent claims in U.S. Patent No. 12146175 B2 anticipates instant claims 1-20. Patent claim 1 recites “d) incubating the supernatant of the fermentation broth of c) for at least 1 h at a temperature between 0° C. and 20° C. for folding of the CLP”. The between 0° C and 20° C temperature range recited in patent claim 1 is narrower in scope compared to the instantly claimed “25˚C or a lower temperature” recited in claim 1 in line 6. Therefore, the nonstatutory double patenting rejection over U.S. Patent No. 12146175 B2 is maintained.
Applicant argues that co-pending application 18/682,348 does not disclose the presently claimed feature of purifying the CLP by solvent precipitation in which the CLP is precipitated. One would not have precipitated the CLP using solvent precipitation based on Ramshaw, which discloses keeping the triple helix protein in solution and not denatured. Gopinath would not have been combined with the other references or if combined would have used conditions that do not precipitate the CLP from solution and denature it. See the remarks p. 11 paragraph 2.
This argument is not persuasive because Gopinath is relied upon for teaching the amended claim element that requires solvent precipitation in which the CLP is precipitated, not Ramshaw or the copending claims as argued. Furthermore, Applicant argues that the conditions of Gopinath do not precipitate the CLP from the solution and denature it. However, Applicant has not pointed to evidence and arguments of counsel cannot take the place of factually supported objective evidence (MPEP 2145 or 716.01(c)).
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).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE HUMPHREY can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657
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