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
The preliminary amendment filed 02/07/2024 is entered. Claims 12-20 are new. Claims 1-20 are pending and under consideration in this action.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The priority document was received in English on 02/07/2024. The instant claims are entitled to the effective filing date of 08/09/2021.
Claim Objections
Claims 1, 8 and 10 are objected to because of the following informalities:
Claim 1 is missing a conjunction at the end of step b) and before step c). Claim 1 recites "an amino acid sequence encoding a" in line 3-4, “forming a CLP,” in line 4, and “with a solvent” in line 7, which are extraneous recitations that can be deleted.
Claim 8 recites “e) additionally purifying the CLP, wherein the one or more additional purifications are selected from the group consisting of” in lines 4-5, which is redundant. Claim 8 may be amended to: e) additionally purifying the CLP by one or more techniques selected from the group consisting of:.
Claim 10 recites "the polynucleotide has a nucleotide sequence which is a replicable nucleotide sequence encoding the collagen-like protein", which is extraneous and convoluted. Claim 10 can be amended to recite “wherein the CLP is from Streptococcus pyogenes.”
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.
Claim 1 step a) is indefinite because it unclear whether the fermenting is performed in a fermentation broth or not, because the subsequent step mentions a fermentation broth. Claim 1 further recites "for folding of the CLP" in line 6, which renders the claim indefinite because in one interpretation step b) is requiring the intended outcome of incubating the fermentation broth from step a) to be folding, and under an alternative interpretation step b) requires a subsequent step of CLP folding immediately following incubating a fermentation broth for at least 1 h at 25˚C or lower. Applicant may amend step b) to recite: incubating the 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 step.
Claims 2-20 depend from claim 1 and are rejected for the reasons set forth above.
Claim 2 recites "accumulating the CLP in a medium, wherein a fermentation broth is obtained" 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.
Claim 9 is indefinite because it is an incomplete sentence. Claim 9 recites that the folding of the CLP in b) is performed at a temperature between -80˚C and 25˚C, for a time between 1 h and 48 h, with a CLP-concentration of at least mg/ml. It is unclear if the folding conditions listed in claim 9 are alternatives, all required, or include other unrecited conditions. It is uncertain whether the folding of the CLP in b) requires folding at the same time as incubating or immediately after incubating.
Claim Interpretation
Claim 1 is a method that requires 3 steps. First, a host cell expressing a polynucleotide encoding a collagen-like protein (CLP) is fermented. Second, the fermentation broth in which the host cell was grown, is incubated for at least 1 h at a temperature that is at or below 25˚C. The result or intended purpose of the required incubation is folding of the CLP. Third, the CLP is purified by solvent precipitation.
Claim 5 requires the solvent used for precipitation to be an organic solvent. The instant specification teaches organic solvents like ethanol. See page 2, line 15.
Claim 9 requires folding CLP at a temperature between -80˚C and 25˚C, for a time between 1h and 48h, and/or with a CLP-concentration of at least 1 mg/ml. The claim indicates that folding is an outcome of such incubation conditions.
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 1-6 and 8-19 are rejected under 35 U.S.C. 103 as being unpatentable over Ramshaw (US 2016/0046692), 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 DNA sequence of a 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, wherein the precipitation is achieved by the addition of ammonium sulphate, by adjustment of pH or adjustment of temperature, and/or by use of a polymer. See claims 1 and 20 of Ramshaw. For acidic precipitation, Ramshaw suggests that acetic acid can be used. Ramshaw suggests that the acidification step does not denature the triple helical protein. 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 be a reasonable expectation of success, because Ramshaw suggests that the recombinantly expressed triple-helical proteins remain soluble throughout precipitation (see claim 1 of Ramshaw).
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, Ramshaw teaches precipitating protein through the addition of polyethylene glycol-4000 from a 40% aqueous stock solution (i.e. 60% aqueous solvent). For small non-animal collagens, such as S. pyogenes, a 10% w/v of PEG-4000 is required (i.e. 90% w/v of aqueous solvent). See [0186]. Thus, Ramshaw teaches a precipitation performed at a solvent concentration of at least 5% as instantly claimed.
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].
Regarding claim 5, Ramshaw teaches precipitating host cell materials from the triple-helical protein under acidic condition, wherein the precipitation is achieved by the addition of ammonium sulphate, by adjustment of pH or adjustment of temperature, and/or by use of a polymer. See claims 1 and 20 of Ramshaw. For acidic precipitation, Ramshaw suggests that acetic acid (i.e. an organic solvent) can be used. See [0126].
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, which is less than 0.9 and less than 0.7 as instantly claimed.
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].
Although Ramshaw does not explicitly teach folding, Ramshaw does teach an incubation at temperatures between -80˚C and 25˚C, and for a time between 1h and 48h. Thus, Ramshaw's incubation necessarily results in folding of the CLP.
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, Ramshaw teaches precipitating protein through the addition of polyethylene glycol-4000 from a 40% aqueous stock solution (i.e. 60% aqueous solvent). For small non-animal collagens, such as S. pyogenes, a 10% w/v of PEG-4000 is required (i.e. 90% w/v of aqueous solvent). See [0186]. Thus, Ramshaw teaches a precipitation performed at a solvent concentration of at least 15% as instantly claimed.
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. Ramshaw suggests that the thermal stability of the triple-helical protein is maintained under the acidic precipitating conditions at a temperature at least 10°C below the Tm of the triple-helical protein. See [0029]. The melting temperature of the collagen-like domain of S. pyogenes (Scl2) at an acidic pH is 25.7˚C. See table 1 in paragraph [0039]. Thus, Ramshaw teaches a 4˚C-30˚C precipitation range, which overlaps with the instantly required 20˚C or less range; and Ramshaw further suggests that an acidic precipitation of Scl2 would occur at 15.7˚C, which is less than 20˚C.
Regarding claim 16, Ramshaw teaches freeze drying S. pyogenes collagen. See [0190].
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.
Claims 7 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Ramshaw (US 2016/0046692), as applied to claims 1-6, 8-19 above, and further in view of Gopinath (European Biophysics Journal, 2014, 43(12), 643-652)
Regarding claim 7, Ramshaw teaches a purification method comprising precipitating the host cell materials from the triple-helical protein under acidic condition, wherein the precipitation is achieved by the addition of ammonium sulphate, by adjustment of pH or adjustment of temperature, and/or by use of a polymer. See claims 1 and 20 of Ramshaw. For acidic precipitation, Ramshaw suggests that acetic acid can be used. Ramshaw suggests that the acidification step does not denature the triple helical protein. See [0126].
Ramshaw does not teach solvents for solvent precipitation selected from 2-propanol, ethanol, acetone, dimethyl sulfoxide, and mixtures thereof.
Gopinath teaches precipitating collagen in ethanol. See, for example, 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 pages 644-645. Gopinath teaches that the triple helix survives in 40% ethanol when collagen is incubated at low temperature (5˚C). See the right column on page 649. Furthermore, Gopinath suggests that increasing the concentration of ethanol to 30 and 40 % leads to rapid precipitation. See the left column on page 650.
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 replace the acid precipitation of Ramshaw with the ethanol precipitation of Gopinath. One would be motivated to do so because Gopinath suggests that ethanol can be used to rapidly precipitate collagen without affecting its helical structure . There would be 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 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.
Ramshaw and Gopinath do not teach folding of the CLP with a concentration of at least 4 mg/ml.
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 protein of Ramshaw in view of Gopinath. One would be motivated to concentration the triple-helical protein of Ramshaw because Ramshaw suggests applying a concentration technique as an intermediary step. There would be a reasonable expectation of success because Gopinath demonstrates preparing collagen to concentrations of 4 mg/mL.
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 not more than 25˚C and purifying the CLP by solvent precipitation (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 (i.e. an organic polar solvent). See [0126]. Evidentiary reference Frontier discloses that acetic acid has a relative polarity of 0.648. See page 1 of Frontier (relevant to instant claims 1, 5-6, 9, 14-15, 18-19). Ramshaw teaches removing intact host cells from the secreted-helical protein. See [0099] (relevant to instant claim 2). Ramshaw teaches precipitating protein through the addition of polyethylene glycol-4000 from a 40% aqueous stock solution (i.e. 60% aqueous solvent). See [0186] (relevant to instant claims 3 and 12). Ramshaw teaches acidic precipitating conditions at a temperature at least 10°C below the Tm (i.e. melting temperature) of the triple-helical protein. See [0029]. The melting temperature of Scl2 at an acidic pH is 25.7˚C. See table 1 in paragraph [0039] (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.
Conclusion
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