DETAILED ACTION
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 .
Specification
The disclosure is objected to because of the following informalities:
MPEP 2413.04 provides the following:
Since the "Sequence Listing XML" is not the text of the specification, but rather is sequence data in an XML file format, an incorporation by reference statement is needed to ensure that the content of the "Sequence Listing XML," submitted to the USPTO as an XML file, is considered part of the disclosure capable of providing 35 U.S.C. 112(a) support for the disclosure and any claims relating to nucleotide and/or amino acid sequences. The incorporation by reference statement identifies: (i) the name of the file; (ii) the date of creation of the file; and (iii) the size of the file in bytes. Note that this requirement pertaining to applicant submission of a "Sequence Listing XML" does not apply to a sequence listing that is part of an international application and communicated to the USPTO under PCT Article 20, for a national phase application.
Appropriate correction is required.
Claim Objections
Claims 2, 3, 4, 5, 8, 10, 11, 12, 13, 14, 17, and 18 are objected to because of the following informalities:
Claim 5 should be amended as below to insert a common and adjust articles as indicated:
A method for preparing L-lysine, comprising: expressing the protein according to claim 1 in a recipient biological cell, or increasing a content or activity of the protein in a [[the]] recipient biological cell to obtain a recombinant biological cell, or increasing a content or activity of the protein shown in SEQ ID NO: 2 in a [[the]] recipient biological cell, to obtain a recombinant biological cell; and culturing the recombinant biological cell to obtain the L-lysine.
Either recited act of expressing the protein of claim 1 or increasing activity or content of the protein of SEQ ID NO: 2 is understood to produce alternate embodiments of a recombinant cell, which is then cultured in the culturing step. However, this must be clarified by addition of a comma as indicated. As further explained below under rejections under 35 U.S.C. 112(d), claim 5 recites three separate Markush group species in the alternative. As such, claim 5 should be amended to recited “a” recipient cell in each Markush species since each Markush species is a separate structure
In claims 2 and 11, a conjunction “or” should appear between paras. B3) and B4).
In claims 3 and 17, a conjunction “or” should appear between paras. b12) and b13). In last line of claims 3 and 17, “used for encoding” should be amended to “encodes.”
In claims 4, 12 and 18, “the expression cassette in B2) is” should be amended to “the expression cassette in B2) is” should be amended to “the expression cassette in B2) comprises.” Further, in claims 4, 12 and 18, a conjunction “or” should appear after semicolon at end of line 2.
Claim 8 (line 2), claim 10 (line 2), claim 13 (line 2), and claim 14 (line 2) all recite “the protein” that is understood to be the protein having SEQ ID NO: 4 recited in claim 1 as indicated in claim 5. However, claim 5 also recites “the protein shown in SEQ ID NO: 2,” which is a different protein. The claims should be amended in a manner to better distinguish that two different “the proteins” are recited in the claims, such as a first protein and a second protein or some other amendment that better indicates that “the protein” as recited in the protein of SEQ ID NO: 4.
In claims 3 (line 3) and claim 11 (line 4), “a DNA molecule shown in SEQ ID NO: 3” should recite “a DNA molecule comprising SEQ ID NO: 3.” Claims 1 and 2 from which claims 3 and 11 depend requires any nucleic acid molecule to encoding the protein of claim 1. As such, the claim language should indicate that the whole sequence of SEQ ID NO: 3 is required wherein “a DNA molecule shown in SEQ ID NO: 3” may be interpreted as including subsequences.
In claims 4, 12 and 18, the claims should be amended as follows (last lines of claims): “or a recombinant microorganism obtained by introducing the nucleic acid molecule in B1) into a [the] microorganism and expressing the nucleic acid molecule.” Claims 4, 12 and 18 recite a composition of matter and not a method. As such, the structure of the claims should not be defined by verbal acts such as “introduction,” although recitation of a product-by-process is permissible. In the alternative, the claim can simply recite “a microorganism comprising a nucleic acid molecule in B1). Further, two separate Markush species of a microorganism are understood as recited in the in claims 4, 12 and 18 such that each Markush species should recite “a” microorganism since each Markush species is structurally distinct.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 3, 12 and 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 3 and 17 recite a DNA molecule “hybridizing with the nucleotide sequence . . . under stringent conditions.” Page 3 of the specification states “stringent conditions can be as follows.” However, “can be” is exemplary only and not limiting. There is no limiting understanding of what constitutes “stringent conditions” in the art. As such, an ordinarily skilled artisan cannot determine how to avoid infringement of claims 3 and 17 in the absence of a specific definition for “under stringent conditions” that is not provided by the specification or otherwise extant in the art. Claim 12 is understood as including a DNA molecule “hybridizing with the nucleotide sequence . . . under stringent conditions” as an embodiment of “the nucleic acid molecule in B1).” While any nucleotide sequence embodiment must encode the protein of claim 1, which is 100% identical to SEQ ID NO: 4, due to the degeneracy of the genetic code it is unclear how much change from the sequence of SEQ ID NO: 3 that an embodiment of b13) of claims 3 and 17 can be such that an ordinarily skilled artisan cannot determine how to avoid infringement.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5-10 and 13-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The rejected claims all depend from claim 1. Claim 5 recites a Markush with three Markush species denoted by underline, double-underline and dashed underline below, respectively:
5. A method for preparing L-lysine, comprising: expressing the protein according to claim 1 in a recipient biological cell, or increasing a content or activity of the protein in the recipient biological cell, or increasing a content or activity of the protein shown in SEQ ID NO: 2 in the recipient biological cell to obtain a recombinant biological cell; and culturing the recombinant biological cell to obtain the L-lysine.
As such, a complete embodiment of claim 5 is as follows:
A method for preparing L-lysine, comprising: increasing a content or activity of the protein shown in SEQ ID NO: 2 in a recipient biological cell to obtain a recombinant biological cell; and culturing the recombinant biological cell to obtain the L-lysine.
The protein shown in SEQ ID NO: 2 is not (does not read on) the protein recited in claim 1 requiring the amino acid sequence of SEQ ID NO: 4. As such, claim 5 fails to include all the limitations of claim 1 upon which claim 5 depends, the omitted limitation being at least a protein comprising the amino acid sequence of SEQ ID NO: 1. Further, embodiments of claims 6-10 and 13 and 16 can be satisfied with presence of the protein of SEQ ID NO: 2 with the exclusion of the protein of SEQ ID NO: 4.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 6, 7 and 13-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
“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." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.”). Regents of the University of California v. Eli Lilly & Co., 119, F.3d 1559, 1568, 43 USPQ2d 1398, 1405 (Fed. Cir. 1997).
“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.” MPEP 2163(II)(3)(a).
Furthermore, 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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure ‘indicates that the patentee has invented species sufficient to constitute the gen[us].’ See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.’). ‘A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163(II)(3)(a).
Claim 6 recites a plant or an animal cell configured for synthesizing L-lysine. Claim 7 is interpreted as including the features of claim 5 (due to dependency from claim 5) as if the claim read: The method according to claim 5, wherein the recombinant biological cell is yeast, bacterium, algae, fungi, a plant cell, or an animal cell configured for synthesizing the L-lysine, and wherein the bacterium is Corynebacterium glutamicum.
That is, claim 7 does not recite that the recombinant biological cell is C. glutamicum. As such, claim 7 modifies the scope of bacterium as recited in claim 6 to Corynebacterium glutamicum while otherwise not changing the scope of claim 6.
It is noted that there is no evidence of record that introduction or increasing activity of a protein having SEQ ID NO: 2 or 4 imparts L-lysine production to any cell. The specification, in Embodiment 2 (page 39), states:
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That is, the specification indicates that introduction or increasing activity of a protein having SEQ ID NO: 2 or 4 may increase lysine producing in a recipient cell that already produces L-lysine, but that the same is not sufficient to introduce L-lysine producing ability in a recipient cell lacking such activity.
Recitation of “culturing the recombinant biological cell to obtain the L-lysine” is understood as requiring such cell to accumulate some amount of free L-lysine and is not considered to be satisfied by production of proteins containing lysine amino acid residues or tRNA charged with lysine.
In view of the above, in order for a plant cell or an animal cell to be an embodiment of claim 6 or 7, the recipient plant or animal cell must be configured for synthesizing and accumulating free L-lysine. However, the specification contains no description by working embodiment or general discussion regarding how to configure a plant cell or animal cell to accumulate lysine as to provide for the same to be an embodiment of claim 6 or 7.
A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed. In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163(II)(3)(a).
Here, engineering or otherwise providing for certain microorganisms to accumulate L-lysine is well-established in the prior art. However, the same is not established for animal and plant cells as recited. For example, Korosh et al. (Engineering photosynthetic production of L-lysine, Metabolic Eng. 44, 2017, 273-283), provides:
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While many microorganisms have been engineered to accumulate lysine upon culturing, the evidence of record does not support that animal or plant cells are known to be engineered to accumulate lysine. Further, Korosh evidences that certain customizations are required in imparting L-lysine production ability to new classes of cells (Synechococcus cyanobacteria in Korosh). In the absence of any description or direction in the specification, it is unpredictable regarding how to form an embodiment of claim 6 or 7 wherein the recombinant biological cell is a plant or animal operative to obtain (i.e. accumulate) L-lysine upon culturing as required by claim 5. Again, the evidence of record indicates that expression of a protein of SEQ ID NO: 2 or 4 is not sufficient for introducing ability for accumulation of free L-lysine. For this reason, the specification does not contain an adequate written description of the claimed subject matter.
It is recommended that this rejection be overcome by:
Removing recitation of an animal cell and plant cell from claim 6; and
Amending claim 7 to recite “wherein the recombinant biological cell is Corynebacterium glutamicum.”
Statement regarding prior art
The written opinion of the International Search Authority indicates that claims 5-10 lack novelty over Serber et al. (U.S. 2018/0362991 A1) (see IDS) and CN 110869504. U.S. 2018/0362991 A1 and CN 110869504 appear to be largely duplicative disclosures as related to teachings regarding Ncgl2747 such that U.S. 2018/0362991 A1 is discussed below as addressing both references.
Claim 5 is understood as requiring expressing a protein of SEQ ID NO: 2 or 4 in a recipient biological cell already having an ability to produce L-lysine. Introduction or overexpression of a gene encoding SEQ ID NO: 2 or 4 is not sufficient to introduce L-lysine production in C. glutamicum or other recipient cells based on the evidence of record.
Serber, abstract, “Provided are native promoters comprising polynucleotides isolated from Corynebacterium glutamicum, and mutant promoters derived therefrom, which may be used to regulate, i.e., either increase or decrease, gene expression.” “The present specification provides for, and includes, recombinant nucleic acid molecules comprising a promoter polynucleotide sequence selected from the group consisting of SEQ ID NOs:1 to 8 functionally linked to any one of the heterologous target genes identifiable in the Kyoto Encyclopedia of Genes and Genomes (KEGG) as genes involved in metabolic and biosynthetic pathways. The KEGG database is available on the internet at genome.jp/kegg. In an embodiment, the promoter polynucleotide sequences of SEQ ID NOs:1 to 8 are functionally linked to one or more target genes of the lysine biosynthesis pathway as represented in KEGG map number 00300. In an embodiment, the one or more target genes are selected from the Lysine succinyl-DAP biosynthesis pathway, M00016. In an embodiment, the one or more target genes are selected from the lysine acetyl-DAP biosynthesis pathway, M00525. In an embodiment, the one or more target genes are selected from the lysine DAP dehydrogenase biosynthesis pathway, M00526. In an embodiment, the one or more target genes are selected from the lysine DAP aminotransferase biosynthesis pathway, M00527. In an embodiment, the one or more target genes are selected from the AAA pathway biosynthesis pathway, M00030. In an embodiment, the one or more target genes are selected from the lysine biosynthesis pathway from 2-oxoglutarate, M00433 or the lysine biosynthesis pathway mediated by LysW, M00031.” Serber, para. [0046]. None of these genes is NCgl2747.
NCgl2742 is mentioned in Table 2 of Serber as an aminotransferase. “he present specification provides for, and includes, recombinant nucleic acid molecules comprising a promoter polynucleotide sequence selected from the group consisting of SEQ ID NOs:1 to 8 functionally linked to any one of the heterologous target genes from Corynebacterium glutamicum ATCC 13032 provided in Table 2 or any Corynebacterium glutamicum equivalent thereof.” Serber, para. [0049]. However, NCgl2747 is not associated with C. glutamicum for lysine production wherein genes involved in lysine production are discussed above and in Table 3 of Serber.
The above is not deemed to be a sufficient teaching to motivate the introduction of a gene encoding SEQ ID NO: 2 or 4 in a recipient biological cell suitable for L-lysine production as required by claim 5.
Marinhagen et al. (U.S. 2010/0151449 A1) (see IDS), abstract, states:
The invention relates to a method for production of L-amino acids by fermentation. According to the invention, the activity of the alanine transaminase is ether reduced or inhibited, whereby in particular the amino acids L-valine, L-lysine and L-isoleucine are produced with increased yield. Furthermore, the nucleic acids according to seq. No. 1 from position 101 to 1414 are identified as the sequence coding for the alanine transaminase gene. Use of the above permits the production of L-alanine.
“Surprisingly, the goal is attained in that the activity of the alanine transaminase relative to the naturally occurring strain is reduced or completely deactivated, or that the alanine production is reduced. Furthermore, the goal is attained in that an alanine transaminase is identified.” Marinhagen, para. [0008]. “Surprisingly, the yield for the production of amino acids, particularly L-valine, L-lysine and L-isoleucine, can be considerably increased.” Marinhagen, para. [0010]. The primary embodiment disclosed by Marinhagen is in C. glutamicum. Marinhagen, para. [0003].
SEQ ID NO: 1 (positions 101-1414) of Marinhagen is identical to SEQ ID NO: 1 of the specification, which is the wild-type ngcl2747 gene. As described by Marinhagen, the encoding protein is an alanine transaminase, which is also sometimes referred to in the art as alaT.
As such, the prior art affirmatively teaches that activity of the protein encoded by SEQ ID NO: 1 (SEQ ID NO: 2) including proteins with point mutations of the same is detrimental to lysine production.
Other, more recent prior art also discusses that expression of alanine aminotransferase is detrimental to production of amino acids by C. glutamicum (at least amino acids other than alanine). Yu et al. (Metabolic engineering of Corynebacterium glutamicum for producing branched chain amino acids, Microbial Cell Factories 20, 2021, 230) describes production of branched amino acids (BCAAs) by C. glutamicum. “Simultaneous aceE, alaT, and ilvA knockout in C. glutamicum ATCC13869 resulted in a 44-fold increase in l-valine production, and overexpressing ilvBNC1 further improved l-valine production by 87.6%.” Yu, page 5, left col.
As such, there is not deemed to be sufficient motivation to express a protein having SEQ ID NO: 2 or 4 in C. glutamicum or any other organism that accumulates lysine as required by claim 5 wherein the prior art reviewed above indicates that such alanine aminotransferase proteins should expression/activity reduced.
Allowable Subject Matter
Claim 1 is allowed.
The following is an examiner’s statement of reasons for allowance:
Regarding claim 1 and claims depending therefrom that do not depend from claim 5, the written opinion of the International Search Authority indicates claim 1 as having novelty and inventive step wherein there is no apparent prior art teaching the I319F substitution embodied in SEQ ID NO: 4 relative to SEQ ID NO: 2. A search has not revealed any prior art to contradict this finding.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TODD M EPSTEIN whose telephone number is (571)272-5141. The examiner can normally be reached Mon-Fri 9:00a-5:30p.
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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