DETAILED ACTION
Status of the Application
Claims 33-52 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A preliminary amendment of claims 33, 51-52 as submitted in a communication filed on 9/23/2025 is acknowledged.
Applicant’s election with traverse of Group III, claims 34-40, 42-52, drawn in part to a process for producing a cadaverine dicarboxylate salt, wherein the process comprises culturing microorganisms in a modified medium that lacks non-essential ions, and wherein the cadaverine dicarboxylate salt is crystalized by adding isopropanol, the election of 6 carbons for the dicarboxylic acid and sulfate as the inorganic ion, as submitted in a communication filed on 9/23/2025 is acknowledged.
Applicant’s traverse is on the ground that claim 33 has been amended to specify that the process is for producing a cadaverine dicarboxylate salt solution having reduced organic and inorganic impurities, and comprises adding equal or excess equivalents of dicarboxylic acid to obtain lysine dicarboxylate salt crystals in part (c). Applicant states that the subject matter of claim 33 is novel and non-obvious over the teachings of Mimizuka et al. Applicant’s arguments have been fully considered but not deemed persuasive to withdraw the restriction requirement. The restriction requirement is based on the claims as presented at the time the restriction requirement was issued. It is reiterated herein that the technical feature linking Groups I-VI is a process for producing a cadaverine dicarboxylate salt, which was shown by Mimizuka et al. (JP2009207495A published 9/17/2009; cited in the IDS) to lack novelty or inventive step since Mimizuka et al. teach a process for producing a cadaverine dicarboxylic acid salt by culturing a lysine-producing organism, such as C. glutamicum, adding a dicarboxylic acid, wherein the organism also produces a lysine decarboxylase (paragraphs [0030], [0123]-[0128]; see English translation provided). Thus, the technical feature does not make a contribution over the prior art and the claimed inventions do not meet the requirement of unity of invention under PCT Rule 13.2. See also extensive discussion of the teachings of Mimizuka et al. in Claim Rejections – 35 USC § 102 (AIA ) and 103 (AIA ). The requirement is deemed proper and therefore is made FINAL.
Claim 41 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 9/23/2025.
Claims 33 (linking claim), 34-40, 42-52 are at issue and will be examined to the extent they encompass the elected invention.
Priority
Acknowledgment is made of a claim for foreign priority under 35 U.S.C. 119(a)-(d) to PCT/CN2020/079405 filed on 03/14/2020. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
This is the US national application which entered the national stage from PCT/CN2021/080654 filed on 03/14/2021
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 9/23/2025, 6/26/2025, and 11/21/2022 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings submitted on 9/13/2025 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claim 38 is objected to due to the recitation of “wherein the inorganic ion(s) is or”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “wherein the inorganic ion..”. Appropriate correction is required.
Claim 45 is objected to due to the recitation of “(e) crystallizing…”. Since there is only one limitation, to enhance clarity and to be consistent with commonly used claim language, the term should be amended to remove the itemization label “(e)”. Appropriate correction is required.
Claim 47 is objected to due to the recitation of “expressing lysine decarboxylase”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “expressing a lysine decarboxylase”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
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 33-40, 42-52 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 pre-AIA the applicant regards as the invention.
Claim 33 (claims 34-40, 42-52 dependent thereon) is indefinite in the recitation of “having reduced organic and inorganic impurities” for the following reasons. The term “reduced” is a relative term and the claim fails to provide the basis for comparison (i.e., reduced compared to what?). For examination purposes, no patentable weight will be given to the term. Correction is required.
Claim 33 (claims 34-40, 42-52 dependent thereon) is indefinite in the recitation of “adding equal or excess equivalents of dicarboxylic acid…” for the following reasons. It is unclear as to where the dicarboxylic acid is being added. Step (b) refers to a fermentation step where cells are being cultured and a fermentation broth is formed. Therefore, one cannot determine if the dicarboxylic acid is being added to the entire fermentation broth with cells included, or if the dicarboxylic acid is added to a fermentation broth that lacks microorganisms. Correction is required.
Claim 33 (claims 34-40, 42-52 dependent thereon) is indefinite in the recitation of “reduced inorganic ion content as compared to a lysine inorganic salt stream obtainable via a corresponding process in which an inorganic anion is substituted for the dicarboxylate anion in the buffering system” for the following reasons. The claim requires the comparison to be made with a lysine inorganic salt stream that is not required to be obtained by a particular process since the term “obtainable” can be interpreted as “can be obtained”. In addition, even if the lysine inorganic salt stream is obtained by a process, it is noted that “a corresponding process in which an inorganic anion is substituted for the dicarboxylate anion in the buffering system” encompasses a genus of process. Therefore, the basis of comparison is variable, making the determination as to what is encompassed or excluded impossible. A lysine dicarboxylate stream can have a reduced inorganic ion content if the comparison is made with process A in which an inorganic anion is replaced with dicarboxylate anion X, and at the same time not have a reduced inorganic ion content if the comparison is made with process B in which an inorganic anion is replaced with dicarboxylate anion Y. For examination purposes, no patentable weight will be given to the term “the lysine dicarboxylate salt stream having reduced inorganic ion content as compared….in the buffering system”. Correction is required.
Claim 33 (claims 34-40, 42-52 dependent thereon) is indefinite in the recitation of “by adding the ammonium dicarboxylate buffering system to said solution” for the following reasons. There is no antecedent basis for the/said solution. Also, the only mention of an ammonium dicarboxylate buffering system is found in step (a), where the culture medium is required to comprise an ammonium dicarboxylate buffering system. Therefore, as written, it is unclear if step (d) requires the same ammonium dicarboxylate buffering system that is mentioned in step (a). For examination purposes, no patentable weight will be given to the term “by adding the ammonium ….salt solution”. Correction is required.
Claim 35 is indefinite in the recitation of “non-essential inorganic ions” for the following reasons. The term “non-essential “ is unclear in the absence of a statement indicating the action/activity associated with the term “essential”. For example, an iron ion may be essential for growth but it may be non-essential for producing compound X. Therefore, the same ion may be encompassed or excluded depending on what the ion is essential or non-essential for. For examination purposes, no patentable weight will be given to the term and claim 35 will be interpreted as a duplicate of claim 33. Correction is required.
Claim 37 is indefinite in the recitation of “non-essential inorganic anions” for the following reasons. The term “non-essential” is unclear in the absence of a statement indicating the action/activity associated with the term “essential”. For example, an anion may be essential for growth but it may be non-essential for producing compound X. Therefore, the same anion may be encompassed or excluded depending on what the anion is essential or non-essential for. For examination purposes, no patentable weight will be given to the term “(i) does not comprise the addition of any further sources…in the lysine dicarboxylate salt stream, and/or”. Correction is required.
Claim 38 is indefinite in the recitation of “wherein the inorganic ion(s) is or comprises phosphate, sulfate and/or chloride anions” for the following reasons. As known in the art, an ion is an atom or a molecule with a net electric charge. Therefore, it is unclear as to how an ion can comprise any combination of phosphate, sulfate and chloride anions. In addition, it is unclear as to which inorganic ions are being referred to. Claim 33 refers to a “reduced inorganic ion content” but does not refer to inorganic ions. If the intended limitation is “wherein the inorganic ion is a phosphate, sulfate or chloride anion,” the claim should be amended accordingly. For examination purposes, claim 38 will be interpreted as a duplicate of claim 33. Correction is required.
Claim 42 is indefinite in the recitation of “…cultured in a growth medium formulated to be devoid of non-essential inorganic salts…..after which the growth medium is replaced with said modified culture medium comprising an ammonium dicarboxylate buffering system and being devoid of non-essential inorganic ions” for the following reasons. The term “non-essential” is unclear in the absence of a statement indicating the action/activity associated with the term “essential”. For example, an iron ion/salt may be essential for growth but it may be non-essential for producing compound X. Therefore, the same ion/salt may be encompassed or excluded depending on what the ion/salt is essential or non-essential for. In addition, it is noted that claim 33 requires providing a fermentation broth that comprises microorganisms and a culture medium that comprises an ammonium dicarboxylate buffering system. As known in the art, a fermentation broth implies that this is a broth that is obtained after culturing microorganisms. Therefore, it is unclear if the growth medium obtained after the desired cell mass is reached is the same fermentation broth of step (a) in claim 33. If so, it is also unclear as to the term “after which the growth medium is replaced with said modified culture medium comprising an ammonium dicarboxylate buffering system and being devoid…” further limits the process of claim 33 if step (a) of the process of claim 33 already requires a fermentation broth that comprises a culture medium that comprises an ammonium dicarboxylate buffering system. For examination purposes, claim 42 will be interpreted as a duplicate of claim 33. Correction is required.
Claim 45 is indefinite in the recitation of “…adding a sufficient volume of an alcohol solvent to the solution to increase the yield of cadaverine dicarboxylate salt crystals recovered by at least 20% as compared to a corresponding crystallization process lacking addition of the organic solvent” for the following reasons. There is no antecedent basis for “the organic solvent”. The term “a corresponding crystallization process lacking addition of the organic solvent” encompasses a genus of crystallization processes. Therefore, the basis of comparison is variable, making the determination as to what is encompassed or excluded impossible. The yield of cadaverine dicarboxylate salt crystals recovered can be at least 20% when compared to crystallization process A and not be at least 20% if compared to crystallization process B. For examination purposes, no patentable weight will be given to the term “by adding a sufficient….to increase the yield of cadaverine…..of the organic solvent”. Correction is required.
Claim 47 (claim 49 dependent thereon) is indefinite in the recitation of “…wherein the enzymatic decarboxylation reaction is performed by subjecting the lysine in the lysine dicarboxylate salt stream to viable or intact cells of a microorganism expressing lysine decarboxylase” for the following reasons. Microorganisms are single cell organisms. Therefore, it is unclear as to how one could have cells of a microorganism. In addition, claim 33 states in step (d) that the lysine dicarboxylate salt is subjected to an enzymatic decarboxylation reaction. Claim 47 requires subjecting lysine in the lysine dicarboxylate salt to the enzymatic reaction. Therefore, it is unclear if claim 47 requires conversion of lysine dicarboxylate to lysine, and then subject lysine to the enzymatic reaction. If this is the case, the scope of claim 47 is different from the scope of claim 33. For examination purposes, it will be assumed that claim 47 requires the enzymatic decarboxylation reaction to be carried out by a lysine decarboxylase. Correction is required.
Claim 48 is indefinite in the recitation of “wherein the lysine decarboxylase is encoded by the kdc gene” for the following reasons. There is no antecedent basis for “the lysine decarboxylase” in claim 33. Also, the term “kdc” as written, appears to be generic and not limited to a specific organism. While the gene nomenclature used may be appropriate for an E. coli gene, the use of this nomenclature for genes encoding proteins of identical function in other organisms may not be accurate. As known in the art, genes encoding proteins of identical function in two different organisms may use different designations. For example, the ARO4 gene of Candida albicans encodes a DAHP synthase whereas the E. coli counterpart is the aroF gene. See the abstract of Sousa et al. (Microbiology 148(Pt5):1291-1303, 2002). As such, the use of gene terminology which is applicable to some organisms and not to others as used herein is confusing since one cannot determine if by using this nomenclature, the claim is limiting the organism from which these genes derive to those that use the same nomenclature. For examination purposes, claim 48 will be interpreted as a duplicate of claim 33. Correction is required.
Claim 49 is indefinite in the recitation of “wherein the viable or intact cells of the microorganism expressing…are immobilized” for the following reasons. Microorganisms are single cell organisms. Therefore, it is unclear as to how one could have cells of a microorganism. If the intended limitation is “wherein the viable or intact cells expressing lysine decarboxylase are immobilized”, the claim should be amended accordingly. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 33-40, 42-52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 33-40, 42-52 are directed in part to a process which requires a genus of enzymes that can catalyze a decarboxylation reaction, including a genus of lysine decarboxylases having any structure, to produce cadaverine dicarboxylate. See Claim Rejections under 35 USC 112, second paragraph, for claim interpretation.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is no structural limitation with respect to the members of the genus of proteins required by the claimed process. While the specification in the instant application discloses the lysine decarboxylase of SEQ ID NO: 2 (encoded by the E. coli kdc gene), it provides no clue as to the structural elements required in any enzyme that can catalyze a decarboxylation reaction or any lysine decarboxylase, nor does it teach which structural elements of the protein of SEQ ID NO: 2 are required in any enzyme that can catalyze a decarboxylation reaction or in a lysine decarboxylase. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of the polypeptides of SEQ ID NO: 2 have lysine decarboxylase activity.
The claims encompass a large genus of proteins which are structurally unrelated. A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is no recited structural feature which is representative of all the members of the genus of enzymes recited in the claims, and there is no information as to which are the structural elements within the polypeptide of SEQ ID NO: 2 that are essential for the recited enzymatic activity, or a correlation between structure and function which would provide those unknown structural features. Furthermore, while one could argue that the species disclosed is representative of the structure of all the members of the genus of enzymes required, it is noted that the art teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999) teach that one conservative amino acid substitution transforms a β-ketoacyl synthase into a malonyl decarboxylase and completely eliminates β-ketoacyl synthase activity. Tang et al. (Phil Trans R Soc B 368:20120318, 1-10, 2013) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrate (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001) teach that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the species disclosed is representative of the structure of all the enzymes that can catalyze a decarboxylation reaction, including lysine decarboxylases required by the claimed process.
Due to the fact that the specification only discloses a single species of the genus of enzymes that can catalyze a decarboxylation reaction, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 33-40, 42-52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a process that requires the conversion of lysine dicarboxylate into cadaverine dicarboxylate by using the protein of SEQ ID NO: 2, does not reasonably provide enablement for a process that requires the conversion of lysine dicarboxylate into cadaverine dicarboxylate by using any enzyme that catalyzes the conversion of lysine dicarboxylate into cadaverine dicarboxylate. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 33-40, 42-52 broadly encompass a process for the production of a cadaverine dicarboxylate salt wherein said method requires the conversion of lysine dicarboxylate into cadaverine dicarboxylate by using an enzyme that catalyzes this conversion having any structure, or a lysine decarboxylase having any structure. The enablement provided is not commensurate in scope with the claims due to the extremely large number of proteins of unknown structure encompassed by the claims, and the lack of information regarding the structural elements within the polypeptides of SEQ ID NO: 2 which are required in any enzyme that can catalyze the conversion of lysine dicarboxylate into cadaverine dicarboxylate. In the instant case, the specification enables a process for the production of a cadaverine dicarboxylate salt wherein said method requires the conversion of lysine dicarboxylate into cadaverine dicarboxylate by using the protein of SEQ ID NO: 2.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the protein of SEQ ID NO:2 as a working example. However, the specification fails to provide any clue as to the structural elements required in any enzyme that can catalyze the conversion of lysine dicarboxylate into cadaverine dicarboxylate, or in any lysine decarboxylase. The specification does not teach those structural features within the protein of SEQ ID NO: 2 that should be present in any lysine decarboxylase. No correlation between structure and function has been presented.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a polypeptide determines its structural and functional properties. While the art discloses a limited number of lysine decarboxylases, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any enzyme that catalyzes the conversion of lysine dicarboxylate into cadaverine dicarboxylate or any lysine decarboxylase.
The art clearly teaches that (a) determining function based solely on structural homology, and (b) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved are highly unpredictable. For example, Singh et al. (Current Protein and Peptide Science 19(1):5-15, 2018) disclose different protein engineering approaches and state that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility and conformational changes (page 11, left column, last paragraph). Sadowski et al. (Current Opinion in Structural Biology 19:357-362, 2009) teach that much of the problem in assigning function from structure comes from functional convergence, where although a stable structure is required to perform many functions it is not always necessary to adopt a particular structure to carry out a particular function (page 357, right column, first full paragraph). Sadowski et al. further explain that the unexpected and significant difficulties of predicting function from structure show that the potential of structural models for providing novel functional annotations has not yet fully realized. Sadowski et al. also states that while a few successes have been achieved which required manual intervention, the ability to vary the requirements for specificity in prediction means that it is difficult to determine how useful the end result may be for the user (page 361, left column, first full paragraph). The teachings of Singh et al. and Sadowski et al. are further supported by the teachings of Witkowski et al., Tang et al. and Seffernick et al. already discussed above, where it is shown that even small amino acid changes result in enzymatic activity changes.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a polypeptide and enzymatic assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find a protein with the desired enzymatic activity. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, and/or (ii) a correlation between structure and lysine decarboxylase activity, one of skill in the art would have to test an essentially infinite number of proteins to determine which ones have the desired functional characteristics.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Claim Rejections - 35 USC § 102 (AIA )
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.
Claims 33-35, 37-40, 42, 45-52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mimizuka et al. (JP-2009-207495A published 9/17/2009; cited in the IDS). The Examiner will use the English translation provided with this action when referring to specific teachings relevant to the instant claims.
Claims 33, 34, 35, 38, 42, 48 as interpreted are directed in part to a process for producing a cadaverine dicarboxylate salt, wherein said process comprises (a) fermenting a microorganism in a culture medium that comprises an ammonium dicarboxylate buffering system and a carbon source, wherein the pH of the fermentation is controlled by adding ammonium hydroxide to produce lysine, (b) adding equal or excess equivalents of dicarboxylic acid to obtain an aqueous solution of dissolved lysine dicarboxylate salt crystals to obtain a lysine dicarboxylate salt stream, and (c) subjecting the lysine dicarboxylate salt stream to an enzymatic decarboxylation reaction to obtain a cadaverine dicarboxylate salt solution while maintaining the pH at a level to allow the reaction to occur using an ammonium dicarboxylate buffering system. Claims 37, 39 and 40 are directed in part to the process of claim 33 as described above, wherein the process does not require (i) a purification step to remove inorganic ions, (ii) does not comprise the use of a carbonate buffering system and/or does not comprise carbonate or carbonate anions, or (iii) does not comprise a distillation step to purify lysine. Claims 45-46 are directed in part to the process of claim 33 wherein the process further requires the crystallization of cadaverine dicarboxylate salt by adding methanol, ethanol or isopropanol. Claims 47, 49 as interpreted are directed to the process of claim 33 as described above, wherein the enzymatic decarboxylation reaction is carried out by a lysine decarboxylase, wherein the lysine decarboxylase is present in viable or intact cells, wherein said cells can be immobilized. Claims 50-52 as interpreted are directed in part to the process of claim 33, wherein the dicarboxylate in the buffering system and/or the dicarboxylic acid added is adipic acid. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
Mimizuka et al. teach a process for the production of a cadaverine dicarboxylate salt (page 6, paragraphs [0021]-[0022]). Mimizuka et al. teach a lysine fermentation where ammonia (ammonium hydroxide) and a dicarboxylic acid are used for pH control (page 7, paragraphs [0029]-[0030]). Mimizuka et al. teach that the culture medium comprises a carbon source (page 8, paragraph [0031]). Mimizuka et al. teach the dicarboxylic acid to be adipic acid (page 9, paragraphs [0038]-[0039]). Mimizuka et al. teach the addition of the dicarboxylic acid to the solution comprising lysine to form lysine dicarboxylate at a ratio of lysine to the dicarboxylic acid of 1:0.5 (equal equivalent) to 1:0.75 (excess equivalent) (page 9, paragraph [0040]). Mimizuka et al. teach the conversion of the L-lysine dicarboxylate to cadaverine dicarboxylate by using a lysine decarboxylase (page 16, paragraph [0073]). Mimizuka et al. teach the use of the dicarboxylic acid and ammonia to control the pH during the reaction of the lysine decarboxylase (pages 9-10, paragraph [0040]). Mimizuka et al. teach the crystallization of the cadaverine dicarboxylate salt by adding an organic solvent such as methanol, ethanol or isopropanol (page 17, paragraphs [0079]-[0082]). Mimizuka et al. teach a recombinant cell (viable and intact cell) that produces the lysine decarboxylase (page 13, paragraph [0057]) and the immobilization of said recombinant cell for repeated use of the enzyme (page 15, paragraph [0067]-0070]). Mimizuka et al. do not teach a process that requires (i) a purification step to remove inorganic ions, (ii) the use of a carbonate buffering system and/or does not comprise carbonate or carbonate anions, or (iii) a distillation step to purify lysine. Therefore, the process of Mimizuka et al. anticipates the instant claims as written/interpreted.
Claim Rejections - 35 USC § 103 (AIA )
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 of this title, 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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Mimizuka et al. (JP-2009-207495A published 9/17/2009; cited in the IDS).
The teachings of Mimizuka et al. have been discussed above. Mimizuka et al. do not specifically teach a total ammonium concentration between 0.05% and 0.5% w/v.
Claim 36 is directed in part to the process of claim 33 wherein the ammonium hydroxide is added to maintain a total ammonium concentration between 0.05% and 0.5% w/v. While Mimizuka et al. do not teach the specific total ammonium concentration recited, it is noted that it would have been routine optimization to arrive to the recited range since all that would have been required is to test the process of Mimizuka et al. with different ammonium concentrations. Furthermore, it is well settled that routine optimization is not patentable, even though it results in significant improvement over the prior art (see MPEP 2144.05 (II)). One of ordinary skill in the art has a reasonable expectation of success at arriving to these concentrations because ammonium hydroxide is being used for pH control in a medium that is buffered. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Mimizuka et al. (JP-2009-207495A published 9/17/2009; cited in the IDS) in view of Ying et al. (U.S. Publication No. 2021/0147887 published 5/20/2021, priority date 3/13/2020).
The teachings of Mimizuka et al. have been discussed above. Mimizuka et al. do not teach an immobilized bacterium that produces lysine. Ying et al. teach a method for the production of lysine by an immobilized fermentation of a recombinant C. glutamicum (Abstract). Ying et al. teach a genetic modification to enhance the attachment of C. glutamicum to a solid carrier (page 2, paragraphs [0031]-[0039]. Ying et al. teach that an immobilized fermentation allows continuous production of lysine in a large scale with bacteria that can be reused at higher yields when compared with suspended cells (page 3, paragraphs [0044]-[0045]).
Claims 43-44 as interpreted are directed in part to the process of claim 33 wherein the cells that produce lysine are bacterial and immobilized. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the immobilized lysine producing cells of Ying et al. in the method of Mimizuka et al. A person of ordinary skill in the art is motivated to use the immobilized cells of Ying et al. for the benefit of using a reusable cell that allows for higher yields of lysine, which is a precursor of the cadaverine dicarboxylate salt, thus increasing the yield of the cadaverine dicarboxylate salt. One of ordinary skill in the art has a reasonable expectation of success at using the immobilized cells of Ying et al. because Ying et al. teach using their cells for the production of lysine. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
December 23, 2025