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. Preliminary amendment and claims 1-15 filed on 10/11/24 are under consideration in this Office Action.
2. Priority
Receipt is acknowledged of papers (foreign priority filed 4/11/22) submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
3. IDS filed 10/11/24 are considered. A signed copy of the IDS is provided with this Office Action.
4. Drawings
The drawings filed on 10/11/24 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 1-2 & 5-15 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 1-15 are directed to the following claimed genus.
1. A method for preparing an α-branched β′-hydroxy carbonyl compound by reductive aldol reaction, wherein the method comprises the steps: a) providing an α,β-unsaturated carbonyl donor, wherein the α,β-unsaturated carbonyl donor is a coenzyme A thioester of an α,β-unsaturated carboxylic acid; b) providing a carbonyl acceptor, wherein the carbonyl acceptor is an aldehyde; c) performing an enzymatic-catalyzed reductive aldol reaction with the α,β-unsaturated carbonyl donor and the carbonyl acceptor by using a polypeptide capable of catalyzing reductive aldol reactions in the presence of a cofactor, wherein the polypeptide is an enoyl-CoA carboxylase/reductase.
2. The method according to claim 1, wherein the polypeptide is a crotonyl-CoA carboxylase/reductase.
3. The method according to claim 1, wherein the polypeptide comprises at least 95% sequence identity to amino acid sequence SEQ ID NO: 1 or SEQ ID NO:2.
4. The method according to claim 1, wherein the polypeptide comprises the amino acid sequence SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27 or SEQ ID NO: 29.
5. The method according to claim 1, wherein the polypeptide is a wild type crotonyl-CoA carboxylase/reductase.
6. The method according to claim 1, wherein the polypeptide is a crotonyl-CoA carboxylase/reductase obtained from Kitasatospora setae or Caulobacter crescentus.
7. The method according to claim 1, wherein the cofactor is NADPH.
8. The method according to claim 1, wherein the α,β-unsaturated carboxylic acid has the general formula (I): ##STR00021## wherein R.sup.1 is selected from hydrogen, an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, carboxy, aminocarbonyl, thiocarbonyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carboxyalkyl, aminoalkyl, haloalkyl, alkylthioalkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl.
9. The method according to claim 8, wherein R.sup.1 represents —H, cyclo-C.sub.3H.sub.5, cyclo-C.sub.4H.sub.7, cyclo-C.sub.5H.sub.9, cyclo-CH.sub.11, cyclo-C.sub.7H.sub.13, cyclo-C.sub.8H.sub.15, -Ph, —CH.sub.2-Ph, —C.sub.2H.sub.4Ph, —CPh.sub.3, —CH.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3).sub.3, —C.sub.5H.sub.11, —CH(CH.sub.3)—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3).sub.3, —CH(C.sub.2H.sub.5).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3).sub.2, —CH.sub.13, —C.sub.3H.sub.6—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3)—C.sub.3H.sub.7, —CH(CH.sub.3)—CH.sub.2—CH(CH.sub.3).sub.2, —C.sub.7H.sub.15, —C.sub.8H.sub.17, —C(CH.sub.3).sub.2—C.sub.3H.sub.7, —CH(CH.sub.3)—CH(CH.sub.3)—C.sub.2H.sub.5, —CH.sub.2—CH(CH.sub.3)—CH(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3).sub.2—C.sub.2H.sub.5, —CH(CH.sub.3)—C(CH.sub.3).sub.3, —C(CH.sub.3).sub.2—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—C(CH.sub.3).sub.3, —CH═CH.sub.2, —CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH.sub.2, —CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH.sub.2, —CH.sub.2—CH═CH—CH.sub.3, —CH═CH—C.sub.2H.sub.5, —CH═C(CH.sub.3).sub.2, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—CH═CH, —C(CH.sub.3)═CH—CH.sub.3, —CH═CH—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH.sub.2, —C.sub.2H.sub.4—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—C.sub.2H.sub.5, —CH═CH—C.sub.3H.sub.7, —CH.sub.2—CH═CH—CH═CH.sub.2, —CH═CH—CH═CH—CH.sub.3, —C.sub.2H.sub.4—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—C.sub.2H.sub.5, —CH.sub.2—CH═CH—CH═CH.sub.2, —CH═CH—CH═CH—CH.sub.3, —CH═CH—CH.sub.2—CH═CH.sub.2, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —CH.sub.2—CH═C(CH.sub.3).sub.2, —C(CH.sub.3)═C(CH.sub.3).sub.2, —C.sub.2H.sub.4—CH═CH.sub.2, —CH═CH—C.sub.2H.sub.5, —CH═C(CH.sub.3).sub.2, —CH.sub.2—CH═CH—CH.sub.3, —CH═CH—CH═CH.sub.2, —C.sub.3H.sub.6—CH═CH.sub.2, —CH═CH—C.sub.3H.sub.7, —C.sub.4H.sub.8—CH═CH.sub.2, —CH═CH—C.sub.4H.sub.9, —C.sub.3H.sub.6—CH═CH—CH.sub.3, —CH.sub.2—CH═CH—C.sub.3H.sub.7, —C.sub.2H.sub.4—CH═CH—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3)═C(CH.sub.3).sub.2, —C.sub.2H.sub.4—CH═C(CH.sub.3).sub.2, —CH.sub.2—C≡CH, —C≡CH, —C≡C—CH.sub.3, —C.sub.2H.sub.4—C≡CH, —C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—CH.sub.3, —C≡C—CH═CH.sub.2, —CH═CH—C≡CH, —C≡C—C≡CH, —C.sub.3H.sub.6—C≡CH, —C≡C—C.sub.3H.sub.7, —C.sub.2H.sub.4—C≡C—CH.sub.3, —CH.sub.2—C≡C—C.sub.2H.sub.5, —CH.sub.2—C≡C—CH═CH.sub.2, —CH.sub.2—CH═CH—C≡CH, —CH.sub.2—C≡C—C≡CH, —C≡C—CH═CH—CH.sub.3, —CH═CH—C≡C—CH.sub.3, —C≡C—C≡C—CH.sub.3, —C≡C—CH.sub.2—CH═CH.sub.2, —CH═CH—CH.sub.2—C≡CH, —C≡C—CH.sub.2—C≡CH, —C(CH.sub.3)═CH—CH═CH.sub.2, —CH═C(CH.sub.3)—CH═CH.sub.2, —CH═CH—C(CH.sub.3)═CH.sub.2, —C(CH.sub.3)═CH—C≡CH, —CH═C(CH.sub.3)—C≡CH, —C≡C—C(CH.sub.3)═CH.sub.2, —C.sub.4H.sub.8—C≡CH, —C≡C—C.sub.4H.sub.9, —C.sub.3H.sub.6—C≡C—CH.sub.3, —CH.sub.2—C≡C—C.sub.3H.sub.7, —C.sub.2H.sub.4Ph, —CH═CH-Ph, —C≡C-Ph, —CH.sub.2NH.sub.2, —CH.sub.2OH, —CH.sub.2SH, —CH.sub.2—CH.sub.2NH.sub.2, —CH.sub.2—CH.sub.2SH, —C.sub.6H.sub.4—OCH.sub.3, —C.sub.6H.sub.4—OH, —CH.sub.2—CH.sub.2—OCH.sub.3, —CH.sub.2—CH.sub.2OH, —CH.sub.2—OCH.sub.3, —CH.sub.2—C.sub.6H.sub.4—OCH.sub.3, —CH.sub.2—C.sub.6H.sub.4—OH, —CH.sub.2R.sup.2, —CH.sub.2CH.sub.2R.sup.2, or —CH.sub.2CH.sub.2CH.sub.2R.sup.2; and R.sup.2 represents —NH.sub.2, —OH, —SH, —F, —Cl, —Br, —I, —CN, —N.sub.3, —OCN, —NCO, —SCN, or —NCS.
10. The method according to claim 1, wherein the carbonyl acceptor has the general formula (II): ##STR00022## wherein R.sup.3 represents —H, —CH.sub.3, —C.sub.2H.sub.5, —C.sub.3H.sub.7, —CH(CH.sub.3).sub.2, —C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3).sub.2, —CH(CH.sub.3)—C.sub.2H.sub.5, —C(CH.sub.3).sub.3, —C.sub.5H.sub.11, —CH(CH.sub.3)—C.sub.3H.sub.7, —CH.sub.2—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—CH(CH.sub.3).sub.2, —C(CH.sub.3).sub.2—C.sub.2H.sub.5, —CH.sub.2—C(CH.sub.3).sub.3, —CH(C.sub.2H.sub.5).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3).sub.2, —C.sub.6H.sub.13, —C.sub.3H.sub.6—CH(CH.sub.3).sub.2, —C.sub.2H.sub.4—CH(CH.sub.3)—C.sub.2H.sub.5, —CH(CH.sub.3)—C.sub.4H.sub.9, —CH.sub.2—CH(CH.sub.3)—C.sub.3H.sub.7, —CH(CH.sub.3)—CH.sub.2—CH(CH.sub.3).sub.2, -Ph, or —CH.sub.2-Ph.
11. The method according to claim 1, wherein the carbonyl acceptor is selected from the group comprising or consisting of formaldehyde, acetaldehyde and propionaldehyde.
12. The method according to claim 1, wherein the α,β-unsaturated carboxylic acid is selected from the group comprising or consisting of crotonic acid (trans-2-butenoic acid), trans-cinnamic acid, 5-chloro-2-pentenoic acid, trans-2-hexenoic acid, 5-methyl-2-hexenoic acid, trans-2-penten-4-ynoic acid and penta-2,4-dienoic acid.
13. The method according to claim 1, wherein the enzyme-catalyzed reductive aldol reaction is performed in the presence of an acyl-CoA oxidase.
14. The method according to claim 1, further comprising the following step: d) performing a hydrolysis reaction with the coenzyme A thioester of the α-branched β′-hydroxy carbonyl compound under basic conditions or by using a thioesterase.
15. The method according to claim 1, wherein the α-branched β′-hydroxy carbonyl compound has the general formula (IIIa) and the α-branched β′-hydroxy acyl-CoA has the general formula (IIIb): ##STR00023## and R.sup.1, R.sup.2, and R.sup.3 have the same meanings as defined in any one of the claims 8-10.
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, only provides description of: A method for preparing an α-branched β′-hydroxy carbonyl compound by reductive aldol reaction, wherein the method comprises the steps: a) providing an α,β-unsaturated carbonyl donor, wherein the α,β-unsaturated carbonyl donor is a coenzyme A thioester of an α,β-unsaturated carboxylic acid; b) providing a carbonyl acceptor, wherein the carbonyl acceptor is an aldehyde; c) performing an enzymatic-catalyzed reductive aldol reaction with the α,β-unsaturated carbonyl donor and the carbonyl acceptor by using a polypeptide capable of catalyzing reductive aldol reactions in the presence of a cofactor, wherein the polypeptide is an enoyl-CoA carboxylase/reductase, wherein the enoyl-CoA carboxylase/reductase (or Crotonyl-CoA carboxylase/reductase) comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 (Kitasatospora setae) or Crotonyl-CoA carboxylase/reductase of SEQ ID NO: 2 (Caulobacter crescentus), and wherein α-branched β′-hydroxy carbonyl compound is 2-(hydroxymethyl) butyryl CoA (2-HMBA-CoA).
The specification does not contain any disclosure or description of the structure and function of all amino acid sequences of enoyl-CoA carboxylase/reductase or an or Crotonyl-CoA carboxylase/reductase from any source, or an enoyl-CoA carboxylase/reductase or Crotonyl-CoA carboxylase/reductase derivative(s), derived from such a sequences by insertion, deletion or substitution with limit to the extent of modifications to aid in a method of making 2-(hydroxymethyl) butyryl CoA (2-HMBA-CoA).
The few enzyme species disclosed from SEQ ID NO: 1 (Kitasatospora setae) or Crotonyl-CoA carboxylase/reductase of SEQ ID NO: 2 (Caulobacter crescentus) are not representative of the genus of method steps involving a numerous method limitation that remain undescribed. 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 Crotonyl-CoA carboxylase/reductase 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 Crotonyl-CoA carboxylase/reductase and sequences having varying sequence homology from any source. 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 Crotonyl-CoA carboxylase/reductase activity, to aid in genus of method steps involving a numerous method limitation that remain undescribed.
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.
An important consideration is that structure is not necessarily a reliable indicator of function. In this example, there is no disclosure relating to similarity of structure to conservation of function. General knowledge in the art included the knowledge that some amino acid variations are tolerated without losing a protein’s tertiary structure. The results of amino acid substitutions have been studied so extensively that amino acids are grouped in so-called “exchange groups” of similar properties because substituting within the exchange group is expected to conserve the overall structure. For example, the expectation from replacing leucine with isoleucine would be that the protein would likely retain its tertiary structure. On the other hand, when non-exchange group members are substituted, e.g., proline for tryptophan, the expectation would be that the substitution would not likely conserve the protein’s tertiary structure. Given what is known in the art about the likely outcome of substitutions on structure, those in the art would have likely expected the applicant to have been in possession of a genus of proteins having a tertiary structure similar to SEQ ID NO: 1 or 2 although the claim is not so limited. However, conservation of structure is not necessarily a surrogate for conservation of function. In this case, there is no disclosed correlation between structure and function. There is no disclosure of the active site amino acid residues responsible for the catalytic activity. 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 SEQ ID NO: 1 or 2 to suggest that general similarity of structure confers the activity and that can be employed in: A method for preparing an α-branched β′-hydroxy carbonyl compound by reductive aldol reaction, wherein the method comprises the steps: a) providing an α,β-unsaturated carbonyl donor, wherein the α,β-unsaturated carbonyl donor is a coenzyme A thioester of an α,β-unsaturated carboxylic acid; b) providing a carbonyl acceptor, wherein the carbonyl acceptor is an aldehyde; c) performing an enzymatic-catalyzed reductive aldol reaction with the α,β-unsaturated carbonyl donor and the carbonyl acceptor by using a polypeptide capable of catalyzing reductive aldol reactions in the presence of a cofactor, wherein the polypeptide is an enoyl-CoA carboxylase/reductase or Crotonyl-CoA carboxylase/reductase.
Accordingly, one of skill in the art would not accept the disclosure of SEQ ID NO: 1 or 2 as representative of other proteins having Crotonyl-CoA carboxylase/reductase activity and genus of method steps involving numerous method limitation that remain undescribed. The specification, taken with the pre-existing knowledge in the art of amino acid substitution and the genetic code, fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph.
7. 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.
Claim(s) 1-3 & 5-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stoffel Gabriele, "Investigating and manipulating the reaction mechanism of reductive carboxylases", Dissertation, Philipps-Universität Marburg, 17 October 2019 (2019-10-17), pages i-xii, 1-155, XP93062981.
Stoffel Gabriele teaches: A method for preparing 2-(hydroxymethyl) butyryl CoA (2-HMBA-CoA) by reaction of crotonic acid CoA ester with formaldehyde in the presence of crotonyl CoA carboxylase/reductase (CCR) of Kitasatospora setae. Enoyl-CoA carboxylases/reductases (ECRs) catalyze the reductive carboxylation of enoyl-CoAs and represent the fastest carboxylases known today. We tested whether an aldehyde (carbonyl acceptor) could replace CO2 as the resolving electrophile in the final step of the reaction. The reference also shows that ECR from Kitasatospora setae can utilize formaldehyde as an alternative electrophile thereby forming 2-(hydroxymethyl) butyryl-CoA (2-HMB-CoA). This compound was characterized by mass spectrometry and NMR spectroscopy and confirmed the predicted structure. Enoyl-CoA carboxylases/reductases (ECRs) perform the unique reductive carboxylation of enoyl-CoA thioesters (donor) by oxidizing one equivalent of NADPH. ECRs catalyze the carboxylation of crotonyl-CoA to ethyl malonyl-CoA in the ethylmalonyl-CoA pathway, an important pathway for the assimilation of C2 units in many ecologically relevant bacteria¹. ECRs are also found associated with the biosynthesis of natural products where they produce malonyl-CoA derivatives as extender units². See Chapter III (to its entirety), page 55-71, and Abstract.
Claim 3 is included in this rejection since ECR is isolated from Kitasatospora setae and inherently possesses the amino acid sequence of SEQ ID NO: 1.
8. No claim is allowed.
9. 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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B Mondesi can be reached on 408 918 7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TEKCHAND SAIDHA/
Primary Examiner, Art Unit 1652
Recombinant Enzymes, Hoteling
Telephone: (571) 272-0940
Fax: (571) 273-0940
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