Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
1. Applicant’s election of Group I (claims 1-7, 9-11, 13-14 & 16) without traverse in the reply filed on 3/30/26 is acknowledged.
2. Claims withdrawn:
Claims 17-18, 20-21, 23, 25, 27-30, 32-33 & 35-36 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
3. Priority
Receipt is acknowledged of papers (foreign priority filed 6/25/21) submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
4. Drawings
The drawings filed on 12/22/23 are acknowledged.
5. Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
6. 35 U.S.C. § 112, first paragraph (Written Description)
Claims 1-7, 9-11, 13-14 & 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-7, 9-11, 13-14 & 16 are drawn to the following genus claims:
1. A method of producing 1,4-butanediol, the method comprising: (1) converting succinyl-CoA (SuCoA) to succinate semialdehyde (SSA); (2) converting succinate semialdehyde (SSA) to 4-hydroxybutyrate (4HB); (3) converting 4-hydroxybutyrate (4HB) to 4-hydroxybutyryl CoA (4HBCoA); (4) producing poly-4-hydroxybutyrate (P4HB) by polymerizing two or more of 4-hydroxybutyryl CoA (4HBCoA); and (5) degrading poly-4-hydroxybutyrate to 1,4-butanediol.
2. The method of claim 1, wherein (1) to (4) use any one or more selected from the group consisting of any one or more polypeptides selected from the group consisting of succinate semialdehyde dehydrogenase, 4-hydroxybutyric acid dehydrogenase, 4-hydroxybutyryl-CoA transferase, and poly(3-hydroxyalkanoate) polymerase; a microorganism including the polypeptide, a polynucleotide encoding the polypeptide, or a combination thereof; and a culture thereof.
3. The method of claim 1, further comprising at least one of a TCA cycle, a reductive TCA cycle, and a glyoxylate cycle.
4. The method of claim 3, wherein the TCA cycle includes any one or more selected from the group consisting of (a1) converting pyruvate to acetyl-CoA; (b1) converting acetyl-CoA and oxaloacetate to citrate; (c1) converting citrate to isocitrate; (d1) converting isocitrate to α-ketoglutarate; (e1) converting α-ketoglutarate to succinyl-CoA; and (f1) converting pyruvate to oxaloacetate.
5. The method of claim 1, further comprising (g1) converting phosphoenolpyruvate to oxaloacetate.
6. The method of claim 5, wherein (g1) uses any one or more selected from the group consisting of a phosphoenolpyruvate carboxylase polypeptide; a microorganism including the polypeptide, a polynucleotide encoding the polypeptide, or a combination thereof; and a culture thereof.
7. The method of claim 1, wherein (g1) the converting phosphoenolpyruvate to oxaloacetate is enhanced.
8. (canceled)
9. The method of claim 3, wherein the reductive TCA cycle includes any one or more selected from the group consisting of (a2) converting oxaloacetate to malate; (b2) converting malate to fumarate; (c2) converting fumarate to succinate; and (d2) converting succinate to succinyl-CoA.
10. The method of claim 3, wherein when the method comprises the reductive TCA cycle and (e2) the converting phosphoenolpyruvate to pyruvate is weakened.
11. The method of claim 3, wherein the reductive TCA cycle is enhanced by any one or more selected from the group consisting of the following (I) to (XII): (I) weakening of pyruvate kinase; (II) enhancement of phosphoenolpyruvate carboxylase (PEP carboxylase); (III) enhancement of carbonic anhydrase; (IV) regulation of citrate synthase; (V) enhancement of pyruvate carboxylase; (VI) weakening of NAD.sup.+-dependent malate dehydrogenase; (VII) weakening of NADP.sup.+-dependent malate dehydrogenase; (VIII) weakening of phosphogluconate dehydratase; (IX) weakening of 2-keto-4-hydroxyglutarate:2-keto-3-deoxygluconate 6-phosphate aldolase (KHG/KDPG aldolase); (X) weakening of aspartate aminotransferase; (XI) weakening of glucose-specific PTS enzyme IIBC component; and (XII) enhancement of bicarbonate transporter.
12. (canceled)
13. The method of claim 3, wherein the glyoxylate cycle further includes any one or more selected from the group consisting of (a3) converting isocitrate to glyoxylate and succinate; (b3) converting glyoxylate and acetyl-CoA to malate and CoA; (c3) converting citrate to isocitrate; (d3) converting pyruvate to oxaloacetate; (e3) converting phosphoenolpyruvate to oxaloacetate; (f3) converting oxaloacetate to citrate; (g3) converting malate to fumarate; (h3) converting fumarate to succinate; and (i3) converting succinate to succinyl-CoA.
14. The method of claim 13, wherein at least one of (j3) converting α-ketoglutarate to succinyl-CoA and (k3) converting oxaloacetate to malate is weakened.
15. (canceled)
16. The method of claim 13, wherein the glyoxylate cycle is enhanced by any one or more selected from the group consisting of (i) to (vi): (i) enhancement of citrate synthase; (il) weakening of isocitrate dehydrogenase; (iii) enhancement of isocitrate lyase; (iv) enhancement of isocitrate dehydrogenase kinase/phosphatase; (v) enhancement of malate synthase G; and (vi) enhancement of malate synthase A.
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.
The specification, however, does not provide description of the structure or source of the countless enzymes involved in the various metabolic pathways including TCA cycle, a reductive TCA cycle, and a glyoxylate cycle or even a chemical method of making 1,4-butanediol as in claim 1 – for example. The claims are merely described by what occurs in nature rather than a clear-cut description of what is described in the instant specification.
Merely narrating the pathway steps as in claims -for example - A method of producing 1,4-butanediol, the method comprising: (1) converting succinyl-CoA (SuCoA) to succinate semialdehyde (SSA); (2) converting succinate semialdehyde (SSA) to 4-hydroxybutyrate (4HB); (3) converting 4-hydroxybutyrate (4HB) to 4-hydroxybutyryl CoA (4HBCoA); (4) producing poly-4-hydroxybutyrate (P4HB) by polymerizing two or more of 4-hydroxybutyryl CoA (4HBCoA); and (5) degrading poly-4-hydroxybutyrate to 1,4-butanediol, wherein (1) to (4) use any one or more selected from the group consisting of any one or more polypeptides selected from the group consisting of succinate semialdehyde dehydrogenase, 4-hydroxybutyric acid dehydrogenase, 4-hydroxybutyryl-CoA transferase, and poly(3-hydroxyalkanoate) polymerase; a microorganism including the polypeptide, a polynucleotide encoding the polypeptide, or a combination thereof; and a culture thereof; and further comprising at least one of a TCA cycle, a reductive TCA cycle, and a glyoxylate cycle is not considered an invention or a very non-descript one.
The specification, however, only provides description of a method of producing 1,4-butanediol, the method comprising culturing a recombinant E. coli transformed with SucD, 4HbD (SEQ ID NO: 4, aa), OrfZ (SEQ ID NO: 5, aa), PhaC (SEQ ID NO: 7, aa), PPC , and the encoding gene sequences thereof of SEQ ID NO: 1 to SEQ ID NO: 8, SEQ ID NO: 13, and SEQ ID NO: 14; the recovering poly-4-hydroxybutyrate from the microorganism or culture medium; and the degrading poly-4-hydroxybutyrate to 1,4-butanediol.
The specification does not contain any disclosure or description of the structure and function of all DNA/protein sequences from any source or a derivative derived from such a sequence(s) by insertion, deletion or substitution, and encoding a protein which has the biological activity of producing poly-4-hydroxybutyrate and 1,4-butanediol.
The 4/5 species disclosed are not representative of the genus claimed. According to MPEP 2163, to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v.Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed.Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The scope of each genus includes many members of carbonic anhydrase enzymes with widely differing structural, chemical, and physical characteristics. Furthermore, each genus is highly variable because a significant number of structural differences between genus members exit. The specification does not describe and define any structural features and amino acid sequences commonly possessed by each genus. There is no art-recognized correlation between any structure of a pathway enzymes and undescribed sequences. Those of ordinary skill in the art would not be able to identify without further testing what specific DNA sequences would encode a protein having pathway enzyme(s) activity.
The genus of polynucleotides/DNA/protein from any source and that comprise these DNA/protein molecules and encoding many different proteins may be obtained with the aid of a computer by a skilled artisan. However, there is no teaching or clear guidance. An important consideration is that structure is not necessarily a reliable indicator of function. The instant specification provides no disclosure relating similarity or identity of structure to conservation of function. General knowledge in the art provides guidance to modification of some amino acids that are tolerated without losing a protein’s tertiary structure.
The genus of polypeptides and the encoding polynucleotides and modifications required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of polypeptides in the specification with specific structures having the associated function/activity, however, these sequences cannot be imported into the claims, or since one could use structural homology to isolate those polypeptides and the encoding polynucleotides recited in the claims. The art clearly teaches the “Practical Limits of Function Prediction”:
(a) Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and (iv) conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that “Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Applicants’ are respectfully directed to the problems associated EC Classification in the section “Transferring the EC Classification enzyme to Non-Enzyme Comparisons”; pages 101-102 and Fig. 2a)-b), highlighting the structural and functional heterogeneity based on EC Classification numbers; as the stereo-specificity, substrate-specificity and catalytic properties vary widely.
(b) Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340) also highlight the difficulties associated with “Prediction of protein function from protein sequence and structure”; “To reason from sequence and structure to function is to step onto much shakier ground”, closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein’s role fundamentally (page 323, paragraph 1).
(c) This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polynucleotides and encoded polypeptides do not necessarily share the same function. For example, Witkowski et al., (Biochemistry 38:11643-11650, 1999), teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity.
There is no disclosure of the active site amino acid residues responsible for the catalytic activity. Claims 1-7, 9-11, 13-14 & 16 are further complicated as no reference is made to any structure or proposed modification(s). While general knowledge in the art may have allowed one of skill in the art to identify other proteins expected to have the same or similar tertiary structure, in this case there is no general knowledge in the art about similar proteins to suggest that general similarity of structure confers the activity.
The specification, taken with the pre-existing knowledge in the art fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph.
7. 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 7, 10, 11 & 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 10, 11, 14 & 16 use the word “weakened or weakening”. It is not clear how is conversion of said compound(s) are “weakened” or “results in weakening of compounds”. Clarification is required.
Claims 7, 11 & 16 recite the word “enhanced”. It is not clear how is conversion of said compound(s) are “enhanced”. Clarification is required.
8. Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7, 9-11, 13-14 & 16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon) without significantly more. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at http://www.uspto.gov/patents/law/exam/mdc_examples_nature-based_products.pdf (“Nature-Based Products Examples”) and updated guidance of 2015 https://www.uspto.gov/sites/default/files/documents/ieg-july-2015-update.pdf.
The relevant distinction is the one “between patents that claim the ‘buildin[g] block[s]’ of human ingenuity and those that integrate the building blocks into something more, thereby ‘transform[ing]’ them into a patent-eligible invention. The former ‘would risk disproportionately tying up the use of the underlying’ ideas and are therefore ineligible for patent protection. The latter pose no comparable risk of pre-emption, and therefore remain eligible for the monopoly granted under our patent laws.” See Alice Corp., 110 U.S.P.Q.2d at 1981 (quoting Mayo, 101 U.S.P.Q.2d at 1972, 1965-66).
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2A) whether the claim recites or involves a judicial exception (i.e., a law of nature, natural phenomenon, or natural product); and (2B) whether the claim as a whole recites something that amounts to significantly more than the judicial exception.
Question 1: Yes; the claims are directed to a method.
Question 2A: Yes; the claims are drawn to a method that does not differ from those that exist in nature, e.g. a natural method occurring in Corynebacterium or the genus Escherichia having a enzymatic pathway such as TCA cycle, a reductive TCA cycle, and a glyoxylate cycle for example or a method not even using an organism or enzymatic pathway.
However, any of the endogenous enzyme as utilized in the biosynthetic pathway can naturally expresses any one or more polypeptides selected from the group consisting of succinate semialdehyde dehydrogenase, 4-hydroxybutyric acid dehydrogenase, 4-hydroxybutyryl-CoA transferase, and poly(3-hydroxyalkanoate) polymerase; a microorganism including the polypeptide, a polynucleotide encoding the polypeptide, or a combination thereof; and a culture thereof, and which may also be naturally present.
Question 2B: No; while the claims state “the converting phosphoenolpyruvate to oxaloacetate is enhanced as in claim 7 for example”, or “the method comprises the reductive TCA cycle and (e2) the converting phosphoenolpyruvate to pyruvate is weakened as in claim 10, for example; there is nothing in the claims which differentiates, for example, naturally occurring pathway/cycle is enhance/weakened or modified in host cell (Corynebacterium or the genus Escherichia) as no specific genetic modification is evident. There is nothing in terms of structure and/or function in the limitations which gives rise to a significant or marked difference because as noted above, Corynebacterium or the genus Escherichia possesses all the enzymes as claimed and must produce compound in question and in nature.
9. 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 (i.e., changing from AIA to pre-AIA ) 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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by EP 2534141 (2016) Referenced in the IDS filed 12/22/23.
EP 2534141 (2016) teaches a method for producing 1,4-butanediol, comprising the steps of: converting succinyl-CoA to succinic semialdehyde; converting succinic semialdehyde to 4-hydroxybutyrate; converting 4-hydroxybutyrate to 4-hydroxybutyryl-CoA; polymerizing 4-hydroxybutyryl-CoA to poly-4-hydroxybutyrate; and producing 1,4-butanediol through hydrogenation of poly-4-hydroxybutyrate (see paragraphs [0013] and [0045], example 12, and figure 1). In addition, EP 2534141 discloses a microorganism for producing poly-4-hydroxybutyrate, into which genes are introduced, the genes encoding a succinate semialdehyde dehydrogenase, a succinic semialdehyde
reductase (the same as a 4-hydroxybutyrate dehydrogenase), a 4-hydroxybutyryl-CoA transferase, and a polyhydroxyalkanoate synthase (the same as a (3-hydroxyalkanoate) polymerase)) (see paragraphs [0013], [0041] and [0045], figure 1, and table IA).
With respect to claims 2, EP 2534141 discloses producing poly-4-hydroxybutyrate by using a microorganism into which genes are introduced, the genes encoding a succinate semialdehyde dehydrogenase, a succinic semialdehyde reductase (the same as a 4-hydroxybutyrate dehydrogenase), a 4-hydroxybutyryl-CoA transferase, and a polyhydroxyalkanoate synthase (the same as a (3-hydroxyalkanoate) polymerase)) (see paragraphs [0013], [0041] and [0045], figure 1, and table IA). With respect to claims 3, EP 2534141 indicates that TCA cycle is included in a poly-4-hydroxybutyrate production pathway (see paragraph [0045], example 5, and figure 1).
With respect to claim 4, EP 2534141 teaches that the poly-4-hydroxybutyrate production pathway comprises the steps of: converting pyruvate to acetyl-coA; converting acetyl-coA and oxaloacetate to citrate; converting citrate to isocitrate; converting isocitrate to a-ketoglutarate; and converting a-ketoglutarate to succinyl-coA (see paragraph [0045] and figure 1). With respect to claims 5-7, EP 2534141 teaches that the conversion of phosphoenolpyruvate to oxaloacetate is increased by overexpressing a phosphoenolpyruvate carboxylase (see paragraph [0045], example 5, and figure 1).
10. No claim is allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to TEKCHAND SAIDHA whose telephone number is (571)272-0940. The examiner can normally be reached on M-F 8.00-5.30. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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/TEKCHAND SAIDHA/
Primary Examiner, Art Unit 1652
Recombinant Enzymes, Hoteling
Telephone: (571) 272-0940
Fax: (571) 273-0940
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