DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s preliminary amendment to the claims, filed November 11, 2024, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Claims 15-25 are pending in the application and are being examined on the merits.
Priority
This application is filed under 35 U.S.C. 371 as a national stage of international application PCT/EP2022/064803, filed May 31, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 6, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Specification/Informalities
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at p. 20, line 16 and p. 21, line 12. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification is objected to because there is no brief description of the drawing figures. See 37 CFR 1.74 and MPEP 608.01(f).
Appropriate correction is required.
Claim Objections
Claims 15, 21, and 22 are objected to because of the following informalities:
Claims 15 and 21 are objected to in the recitation of “a concentration of OPS in a batch is at least 1 g/L” and in the interest of improving claim form and consistency, it is suggested that the noted phrase be amended to recite (with markings to show changes made) “a concentration of OPS in the reaction
Claim 22 is objected to on the recitation of “is effected by means of a cysteine sulfonic acid decarboxylase” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite (with markings to show changes made) “is effected by
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.
Claims 15-25 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 15 (claims 16-20 dependent therefrom) and 21 (claims 22-25 dependent therefrom) recite the limitation “the microorganism strain E. coli K12 JM105.”There is insufficient antecedent basis for this limitation in the claim.
Claims 15 (claims 16-20 dependent therefrom) and 21 (claims 22-25 dependent therefrom) are indefinite in the recitation of “the biotransformation is carried out under active pH control.” It is unclear as to what process step(s) and/or process condition(s) are intended by the recitation of “active pH control” and in the interest of advancing prosecution, it is suggested that applicant clarify the meaning of the phrase “the biotransformation is carried out under active pH control.”
Claims 15 (claims 16-20 dependent therefrom) and 21 (claims 22-25 dependent therefrom) are also indefinite in the recitation of “a salt of sulfurous acid (sulfite)” because it is unclear as to whether the parenthetical expression “(sulfite)” is intended as an abbreviation for “sulfurous acid” or is intended to limit the salt of sulfurous acid to a salt of sulfite. In the interest of advancing prosecution, it is suggested that applicant clarify the meaning of the phrase “a salt of sulfurous acid (sulfite).”
Claim 20 is indefinite in the recitation of “L-cysteic acid produced is used in the production of taurine” because the claim fails to recite an active step or steps for using the L-cysteic acid in the production of taurine. Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b). See MPEP 2173.05(q).
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.
Claims 15-25 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
MPEP § 2163 further states that “[s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’"
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
The claims recite (in relevant part) a genus of cysteate synthase (CS) enzymes belonging to enzyme class EC 2.5.1. 76, wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105, and the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4 or an amino acid sequence homologous thereto, and wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity.
The recitation of “an amino acid sequence specified in SEQ ID NO: 4” in the phrase “the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4” in claim 15 is interpreted as any two or more contiguous amino acids of instant SEQ ID NO: 4 and given a broadest reasonable interpretation, the recited “CS enzyme” comprises any two or more contiguous amino acids of SEQ ID NO: 4.
Given that the genus of CS enzymes includes species having essentially unlimited amino acid sequences, the genus is considered to encompass CS enzymes with widely variant amino acid sequences.
The specification discloses the actual reduction to practice of the following representative species of the genus of CS enzymes – a CS enzyme comprising the amino acid sequence of SEQ ID NO: 4 and recombinantly produced by an E. coli K12 JM105 comprising an expression construct for the CS enzyme comprising the amino acid sequence of SEQ ID NO: 4. Other than this single representative species, the specification fail to disclose other CS enzymes that exhibit the characteristics recited in the claims.
Regarding the level of skill and knowledge in the art, the instant specification discloses that whether a heterologously expressed protein will occur in the form of insoluble inclusion bodies or in active form cannot be predicted and depends not only on the primary structure of the protein chain (succession in the amino acid sequence), but also on the expression system and parameters used, by means of which the rate of protein biosynthesis can be controlled (e.g., growth temperature, strength of induction at inducible promotors) (specification at p. 12, lines 13-18). According to the specification, Graham et al. (Biochem. J. 424: 467-478, 2009) disclose that Methanoscarcina acetivorans CS enzyme produced recombinantly in E. coli is enriched as enzymatically inactive protein in so-called inclusion bodies and detectable enzyme activity is only measurable after complicated renaturation of the inclusion bodies (specification p. 1, lines 22-26) and it was surprising that the cysteate synthase from Methanoscarcina acetivorans was produced in enzymatically active form in E. coli, since according to the prior art (Graham et al., 2009) the same protein was only produced in inactive form in inclusion bodies when heterologously expressed in E. coli (specification at p. 12, lines 19-23).
Given that the specification discloses only a single representative species of a widely variant genus of CS enzymes, and there is a high level of unpredictability in the art as evidenced by the disclosure of the instant specification, the single disclosed representative species is considered to be insufficient to describe the widely variant genus. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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 21, 22, 24, and 25 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Feinberg et al. (US 2019/0062757 A1; cited on the IDS filed February 6, 2025; hereafter “Feinberg”).
Applicant’s attention is directed to MPEP 2112.III regarding a rejection under 35 U.S.C. 102 and 103.
Claims 21, 22, 24, and 25 are drawn to a process for producing taurine, comprising:
providing L-cysteic acid, wherein the L-cysteic acid is produced by a reaction of O-phospho-L-serine (OPS) with a salt of sulfurous acid (sulfite) and a cysteate synthase (CS enzyme) belonging to enzyme class EC 2.5.1.76 in a biotransformation,
wherein a concentration of OPS in a batch is at least 1 g/L,
wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105,
wherein the biotransformation is carried out under active pH control and the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4 or an amino acid sequence homologous thereto, and
wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity; and
wherein the L-cysteic acid is decarboxylated.
Given a broadest reasonable interpretation, the recitation of “providing L-cysteic acid, wherein the L-cysteic acid is produced by…wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity” in claim 21 is interpreted as a “product-by-process” limitation. According to MPEP 2113, even 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.
Regarding claims 21, 22, and 25, Feinberg generally teaches a cell-based method for the production of taurine (Title and Abstract). Figure 5 of Feinberg depicts a biosynthetic pathway for production of taurine from L-phosphoserine (OPS) including conversion of OPS to cysteate (i.e., cysteic acid) by cysteate synthase, which belongs to EC 2.5.1.76, and decarboxylation of cysteate to taurine by cysteine sulfinic acid decarboxylase (CSAD), which belongs to EC 4.1.1.29.
Given a broadest reasonable interpretation, the product-by-process limitation “wherein the L-cysteic acid is produced…wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity” following the active step of “providing L-cysteic acid” in claim 21 does not distinguish the recited L-cysteic acid from L-cysteic acid produced according to the biosynthetic pathway of Feinberg.
Regarding instant claim 24, Feinberg does not explicitly teach a molar yield of taurine based on a molar amount of L-cysteic acid used is at least 60%. However, since Feinberg’s method is encompassed by claim 21, it is presumed that a molar yield of taurine based on a molar amount of L-cysteic acid used is at least 60% is an inherent feature or characteristic of Feinberg’s method. Since the Office does not have the facilities for examining and comparing applicants’ process with the process of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed process and the process of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Therefore, the process of claims 21, 22, 24, and 25 is anticipated by or obvious in view of Feinberg.
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.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Feinberg in view of Turano et al. (WO 2011/053764 A2; cited on the attached Form PTO-892; hereafter “Turano”).
Claim 23 is drawn to the process of claim 22, wherein the amino acid sequence of the CSAD enzyme is SEQ ID NO. 6.
The relevant teachings of Feinberg as applied to claims 21, 22, 24, and 25 are set forth above.
Feinberg does not teach the amino acid sequence of the CSAD is SEQ ID NO: 6.
Turano is directed to methods and materials for production of taurine in cells and living organisms (paragraph [20]). Figure 1 as described by paragraph [19] of Turano shows a taurine biosynthetic pathways including conversion of cysteate to taurine by SAD. Turano teaches sulfinoalanine decarboxylase (SAD) belongs to enzyme class 4.1.1.29 (paragraph [135]) and teaches a SAD comprising the amino acid sequence of SEQ ID NO: 8 as an example of a SAD of the taurine biosynthetic pathway (paragraph [23] and claim 4). SEQ ID NO: 8 of Turano is identical to instant SEQ ID NO: 6. Turano acknowledges that SAD is another name for CSAD (paragraph [135]).
In view of the combined teachings of Feinberg and Turano, it would have been obvious to one of ordinary skill in the art before the effective filing date to use the CSAD of SEQ ID NO: 8 of Turano as the CSAD in the method of Feinberg. One would have been motivated and would have expected success because Feinberg taught a cell-based method for the production of taurine, including decarboxylation of cysteate to taurine by CSAD, and Turano taught a CSAD that is suitable for cell-based production of taurine from cysteate.
Therefore, the process of claim 23 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Biochemistry 61:2861-2869 with Supporting Information pp. S1-S68, April 2022; cited on the attached Form PTO-892; hereafter “Liu”).
Claims 15-20 are drawn to a process for producing L-cysteic acid, comprising:
a reaction of O-phospho-L-serine (OPS) with a salt of sulfurous acid (sulfite) and a cysteate synthase (CS enzyme) belonging to enzyme class EC 2.5.1.76 in a biotransformation;
wherein a concentration of OPS in a batch is at least 1 g/L;
wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105;
wherein the biotransformation is carried out under active pH control and the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4 or an amino acid sequence homologous thereto; and
wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity.
Given a broadest reasonable interpretation, the recitation of “wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105” in claim 15 is interpreted as a “product-by-process” limitation. According to MPEP 2113, even 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.
The recitation of “an amino acid sequence specified in SEQ ID NO: 4” in the phrase “the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4” of claim 15 is interpreted as any two or more contiguous amino acids of instant SEQ ID NO: 4 and given a broadest reasonable interpretation, the recited “CS enzyme” comprises any two or more contiguous amino acids of SEQ ID NO: 4.
Regarding instant claim 15, Liu teaches a cysteate synthase from Capnocytophaga ochracea (CapA) (p. 2862, Figure 1). Liu teaches heterologous expression of CapA in E. coli BL21 (DE3) cells followed by purification of CapA (p. 2863, columns 1-2). Liu teaches assaying CapA activity in a reaction mixture comprising (in relevant part) 50 mM Tris-HCl, pH 8.5, 1 mM OPS, 1 mM Na2SO3, and CapA (p. 2863, column 2, middle), which resulted in the production of cysteate (p. 2865, Figure 2). Liu teaches determining the Km of CapA for OPS by varying the concentration of OPS (p. 2863, column 2, bottom) and Figure S4C of Liu at p. S60 shows that the activity of CapA varies with the concentration of OPS.
Given a broadest reasonable interpretation, the product-by-process limitation “wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105” in claim 15 does not structurally and/or functionally distinguish the recited CS enzyme from CapA heterologously produced in E. coli BL21 (DE3) as taught by Liu.
Given a broadest reasonable interpretation, the use of a Tris-HCl, pH 8.5 buffer in the reaction mixture of Liu is considered to be encompassed by “active pH control” in claim 15.
Liu teaches the amino acid sequence of CapA (p. S67, Figure S11), which comprises at least two contiguous amino acids of instant SEQ ID NO: 4 and given a broadest reasonable interpretation, the amino acid sequence of CapA is encompassed by “CS enzyme” in claim 15.
While Liu teaches the activity of CapA is dependent upon the concentration of OPS and teaches a reaction comprising 1 mM OPS (which is approximately 0.2 g/L) for producing cysteate, Liu does not teach a concentration of OPS of at least 1 g/L.
According to MPEP 2144.05.II.A, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In this case, the general conditions of claim 15 are disclosed by Liu and Liu taught determining the Km of CapA for OPS by varying concentration of OPS and taught the activity of CapA is dependent upon the concentration of OPS. In view of the teachings of Liu, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select a workable range of OPS concentrations for determining the Km of CapA for OPS, including a concentration of OPS of at least 1 g/L.
Regarding instant claim 16, Liu teaches heterologous expression of CapA in E. coli BL21 (DE3) cells followed by purification of CapA, which did not encompass a renaturation step (p. 2863, columns 1-2).
Regarding instant claims 17 and 18, the recitation of “the OPS is produced biotechnologically” in claim 17 and “wherein the OPS used in the reaction is produced using a microorganism strain having suppressed activity of the O-phospho-L-serine phosphatase (SerB enzyme) belonging to enzyme class EC 3.1.3.3” in claim 18 are interpreted as product-by-process limitations and do not structurally and/or functionally distinguish from the OPS taught by Liu.
Regarding instant claim 19, Liu does not explicitly teach a molar yield of L-cysteic acid based on a molar amount of OPS used is at least 60%. However, as previously stated, it would have been obvious to one of ordinary skill in the art to practice Liu’s method with a concentration of OPS of at least 1 g/L and it is presumed that a molar yield of L-cysteic acid based on a molar amount of OPS used is an inherent feature or characteristic of practicing Liu’s method with a concentration of OPS of at least 1 g/L.
Regarding claim 20, the recitation of “wherein the L-cysteic acid produced is used in the production of taurine” is interpreted as an intended use limitation and does not require any steps to be performed beyond the steps recited in claim 15. See MPEP 2111.02 for guidance regarding intended use limitations and see MPEP 2111.04 for guidance regarding “wherein clauses” that do not require additional method steps.
Therefore, the process of claims 15-20 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 15-22, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Feinberg and Guo et al. (Computational and Structural Biotechnology Journal 15:161-167, 2017; cited on the attached Form PTO-892; hereafter “Guo”).
Claims 15-20 are drawn to a process for producing L-cysteic acid, comprising:
a reaction of O-phospho-L-serine (OPS) with a salt of sulfurous acid (sulfite) and a cysteate synthase (CS enzyme) belonging to enzyme class EC 2.5.1.76 in a biotransformation;
wherein a concentration of OPS in a batch is at least 1 g/L;
wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105;
wherein the biotransformation is carried out under active pH control and the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4 or an amino acid sequence homologous thereto; and
wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity.
Claims 21, 22, 24, and 25 are drawn to a process for producing taurine, comprising:
providing L-cysteic acid, wherein the L-cysteic acid is produced by a reaction of O-phospho-L-serine (OPS) with a salt of sulfurous acid (sulfite) and a cysteate synthase (CS enzyme) belonging to enzyme class EC 2.5.1.76 in a biotransformation,
wherein a concentration of OPS in a batch is at least 1 g/L,
wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105,
wherein the biotransformation is carried out under active pH control and the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4 or an amino acid sequence homologous thereto, and
wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity; and
wherein the L-cysteic acid is decarboxylated.
Given a broadest reasonable interpretation, the recitation of “wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105” in claims 15 and 21 is interpreted as a “product-by-process” limitation. According to MPEP 2113, even 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.
The recitation of “an amino acid sequence specified in SEQ ID NO: 4” in the phrase “the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4” in claims 15 and 21 is interpreted as any two or more contiguous amino acids of instant SEQ ID NO: 4 and given a broadest reasonable interpretation, the recited “CS enzyme” comprises any two or more contiguous amino acids of SEQ ID NO: 4.
Regarding claims 15, 20-22, and 25, Liu teaches a cysteate synthase from Capnocytophaga ochracea (CapA) (p. 2862, Figure 1). Liu teaches heterologous expression of CapA in E. coli BL21 (DE3) cells followed by purification of CapA, which did not encompass a renaturation step (p. 2863, columns 1-2). Liu teaches assaying CapA activity in a reaction mixture comprising (in relevant part) 50 mM Tris-HCl, pH 8.5, 1 mM OPS, 1 mM Na2SO3, and CapA (p. 2863, column 2, middle), which resulted in the production of cysteate (p. 2865, Figure 2).
Given a broadest reasonable interpretation, the product-by-process limitation “wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105” in claims 15 and 21 does not structurally and functionally distinguish the recited CS enzyme from CapA heterologously produced in E. coli BL21 (DE3) as taught by Liu.
Given a broadest reasonable interpretation, the use of a Tris-HCl, pH 8.5 buffer in the reaction mixture of Liu is considered to be encompassed by “active pH control” in claims 15 and 21.
Liu teaches the amino acid sequence of CapA (p. S67, Figure S11), which comprises at least two contiguous amino acids of instant SEQ ID NO: 4 and given a broadest reasonable interpretation, the amino acid sequence of CapA is encompassed by “CS enzyme” in claims 15 and 21.
Liu does not teach a method for producing taurine.
Feinberg generally teaches a cell-based method for the production of taurine (Title and Abstract). Figure 5 of Feinberg depicts a biosynthetic pathway for production of taurine from L-phosphoserine including conversion of L-phosphoserine (OPS) to cysteate by cysteate synthase, which belongs to EC 2.5.1.76, and conversion of cysteate to taurine by cysteine sulfinic acid decarboxylase (CSAD), which belongs to EC 4.1.1.29.
Guo provides a review of in vitro metabolic engineering for biomanufacturing of high-value products (see title). The Abstract of Guo (p. 161) teaches that while many valuable biologically active compound and commodity chemicals have been successfully manufactured using cell-based approaches, the identification and optimization of rate-limiting metabolic pathways for improving product yield is often difficult, which represents a significant and unavoidable barrier of traditional in vivo metabolic engineering. Recently, some in vitro engineering approaches were proposed as alternative strategies to solve this problem. In brief, by reconstituting a biosynthetic pathway in a cell-free environment with the supplement of cofactors and substrates, the performance of each biosynthetic pathway could be evaluated and optimized systematically. According to Guo, cell-free biotechnology is one of the promising approaches that offer complementary advantages to in vivo metabolic engineering (p. 162, column 1, bottom).
In view of the combined teachings of Liu, Feinberg, and Guo, it would have been obvious to one of ordinary skill in the art before the effective filing date to incorporate the method of Liu for producing cysteate into an in vitro biosynthetic pathway with CSAD for production of taurine. One would have been motivated and would have expected success to do this because, while Feinberg teaches an in vivo cell-based method for the production of taurine including the step of converting OPS to cysteate by cysteate synthase and conversion of cysteate to taurine by CSAD, Guo taught that cell-free biotechnology is one of the promising approaches that offer complementary advantages to in vivo metabolic engineering, and Liu taught a cell-free in vitro process for converting OPS to cysteate by cysteate synthase.
Also, while Liu teaches the activity of CapA is dependent upon the concentration of OPS and teaches a reaction comprising 1 mM OPS (which is approximately 0.2 g/L) for producing cysteate, Liu does not teach a concentration of OPS of at least 1 g/L.
According to MPEP 2144.05.II.A, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In this case, the general conditions of claims 15 and 21 are disclosed by Liu and given that Liu taught the activity of CapA is dependent upon the concentration of OPS, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select an optimal or workable range of OPS concentrations for production of cysteate including a concentration of OPS of at least 1 g/L.
Regarding instant claim 16, Liu teaches heterologous expression of CapA in E. coli BL21 (DE3) cells followed by purification of CapA, which did not encompass a renaturation step (p. 2863, columns 1-2).
Regarding instant claims 17 and 18, the recitation of “the OPS is produced biotechnologically” in claim 17 and “wherein the OPS used in the reaction is produced using a microorganism strain having suppressed activity of the O-phospho-L-serine phosphatase (SerB enzyme) belonging to enzyme class EC 3.1.3.3” in claim 18 are interpreted as product-by-process limitations and do not structurally and/or functionally distinguish from the OPS taught by Liu.
Regarding instant claims 19 and 24, the combination of Liu, Feinberg, and Guo does not explicitly teach a molar yield of L-cysteic acid based on a molar amount of OPS used is at least 60% and a molar yield of taurine based on a molar amount of L-cysteate used is at least 60%. However, as previously stated, it would have been obvious to one of ordinary skill in the art to practice Liu’s method with a concentration of OPS of at least 1 g/L and to incorporate the method of Liu for producing cysteate into an in vitro biosynthetic pathway with CSAD for production of taurine and it is presumed that such a method would inherently exhibit a molar yield of L-cysteic acid based on a molar amount of OPS used of at least 60% and a molar yield of taurine based on a molar amount of L-cysteate used of at least 60%.
Therefore, the process of claims 15-22, 24, and 25 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Feinberg and Guo as applied to claims 15-22, 24, and 25 above, and further in view of Turano.
The relevant teachings of Liu, Feinberg, and Guo as applied to claims 15-22, 24, and 25 are set forth above.
The combination of Liu, Feinberg, and Guo does not teach or suggest the amino acid sequence of the CSAD is SEQ ID NO: 6.
Turano is directed to methods and materials for production of taurine in cells and living organisms (paragraph [20]). Figure 1 as described by paragraph [19] of Turano shows a taurine biosynthetic pathways including conversion of cysteate to taurine by SAD. Turano teaches sulfinoalanine decarboxylase (SAD) belongs to enzyme class 4.1.1.29 (paragraph [135]) and teaches a SAD comprising the amino acid sequence of SEQ ID NO: 8 as an example of a SAD of the taurine biosynthetic pathway (paragraph [23] and claim 4). SEQ ID NO: 8 of Turano is identical to instant SEQ ID NO: 6. Turano acknowledges that SAD is another name for CSAD (paragraph [135]).
In view of the teachings of Turano, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify the combined method of Liu, Feinberg, and Guo to use the CSAD of SEQ ID NO: 8 of Turano as the CSAD in the combined method. One would have been motivated and would have expected success because Feinberg taught a cell-based method for the production of taurine, including decarboxylation of cysteate to taurine by CSAD, and Turano taught a CSAD that is suitable for production of taurine from cysteate.
Therefore, the process of claim 23 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim Rejections - 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 21-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 16, 17, 20, and 21 of co-pending application no. 18/712,705 (reference application).
Claims 21-25 of this application are drawn to a process for producing taurine, comprising:
providing L-cysteic acid, wherein the L-cysteic acid is produced by a reaction of O-phospho-L-serine (OPS) with a salt of sulfurous acid (sulfite) and a cysteate synthase (CS enzyme) belonging to enzyme class EC 2.5.1.76 in a biotransformation,
wherein a concentration of OPS in a batch is at least 1 g/L,
wherein the CS enzyme is produced in an enzymatically active form by growth of the microorganism strain E. coli K12 JM105,
wherein the biotransformation is carried out under active pH control and the CS enzyme has an amino acid sequence specified in SEQ ID NO: 4 or an amino acid sequence homologous thereto, and
wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity; and
wherein the L-cysteic acid is decarboxylated.
Given a broadest reasonable interpretation, the recitation of “providing L-cysteic acid, wherein the L-cysteic acid is produced by…wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity” in instant claim 21 is interpreted as a “product-by-process” limitation. According to MPEP 2113, even 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.
Regarding instant claim 21, claim 11 of the reference application recites a process for producing taurine from O-acetyl-L-serine (OAS) using biotransformation, wherein
i) wherein in a first process step (biotransformation 1), L-cysteic acid is produced from O-acetyl-L-serine (OAS) using an enzyme selected from a class of OAS sulfhydrylases (EC 4.2.99.8) in the presence of a salt of sulfurous acid, wherein the biotransformation is carried out under active pH control;
ii) wherein in a second process step (biotransformation 2), L-cysteic acid is decarboxylated to taurine;
wherein the OAS concentration in the batch is at least 10 g/L; and
wherein the OAS sulfhydrylase is CysM.
Given a broadest reasonable interpretation, the product-by-process limitation “wherein the L-cysteic acid is produced…wherein an amino acid sequence homologous to SEQ ID NO: 4 has a sequence identity of at least 50% in relation to SEQ ID NO: 4 and, at the same time, cysteate synthase enzyme activity” following the active step of “providing L-cysteic acid” in instant claim 21 does not distinguish the recited L-cysteic acid from L-cysteic acid produced according to claim 11 of the reference application.
Regarding instant claim 22, claim 16 of the reference application recites (in relevant part) the process of claim 11, wherein the L-cysteic acid is decarboxylated to taurine using an enzyme from the class of L-cysteine sulfinic acid decarboxylases (EC 4.1.1.29).
Regarding instant claim 23, claim 17 of the reference application recites the process of claim 16, wherein the L-cysteine sulfinic acid decarboxylase is SEQ ID NO: 2 or a sequence homologous to this sequence. Instant SEQ ID NO: 6 is identical to SEQ ID NO: 2 of the reference application.
Regarding instant claim 24, claim 21 of the reference application recites the process of claim 11, wherein the molar yield of taurine from the biotransformation of L-cysteic acid in biotransformation 2 is preferably at least 60%.
Regarding instant claim 25, claim 20 of the reference application recites the process of claim 19, wherein all of the process steps take place in one reaction batch.
Therefore, claims 21-25 of this application are unpatentable over claims 11, 16, 17, 20, and 21 of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Status of the claims:
Claims 15-25 are pending.
Claims 15-25 are rejected.
No claim is in condition for allowance.
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/David Steadman/Primary Examiner, Art Unit 1656
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