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 6-25 filed 9/24/25 are under considered in this Office Action.
2. Priority
Applicant’s claim for domestic priority under 35 U.S.C. 119(e), filed 3/18/22, is acknowledged.
3. Drawings
The drawings filed on 10/4/23 are acknowledged.
4. IDS filed 7/5/23 is acknowledged. A signed copy is provided with this Office Action.
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. Claim Rejections: 35 USC § 112(a)
The following is a quotation 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.
Written Description
Claims 6-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
Claims 6-25 are drawn to the following genus claims:
6. (New) A genetically modified Pseudomonas comprising a heterologous D-xylose isomerase pathway wherein the Pseudomonas metabolizes glucose and xylose to produce muconic acid.
7. (New) The genetically modified Pseudomonas of claim 6 wherein the heterologous D- xylose isomerase pathway comprises xylA encoding for D-xylose isomerase, xylB encoding for xylulokinase and xylE encoding for a D-xylose:H+symporter.
8. (New) The genetically modified Pseudomonas of claim 7 wherein the Pseudomonas comprises mutations of the xylE gene.
9. (New) The genetically modified Pseudomonas of claim 8 wherein the xylE gene is from E. coli and comprises mutations resulting in A62V and A455V mutations in the expressed D- xylose:H+symporter.
10. (New) The genetically modified Pseudomonas of claim 8 wherein the expression of a major facilitator superfamily transporter is increased over that of a native Pseudomonas.
11. (New) The genetically modified Pseudomonas of claim 10 wherein the major facilitator superfamily transporter is PP_2569.
12. (New) The genetically modified Pseudomonas of claim 10 wherein aroB encoding for 3- dehydroquinate synthase is overexpressed.
13. (New) The genetically modified Pseudomonas of claim 6 that produces greater than 33 g/L of muconic acid.
14. (New) The genetically modified Pseudomonas of claim 6 that produces muconic acid at a rate of greater than 0.17 g/L/h.
15. (New) The genetically modified Pseudomonas of claim 6 that produces muconic acid at a molar yield of greater than 45 percent from xylose and glucose.
16. (New) The genetically modified Pseudomonas of claim 6 that produces muconic acid at a molar yield of greater than 45 percent from a mixture of xylose and glucose wherein 33 to 40 mol percent of the mixture is xylose.
17. (New) The genetically modified Pseudomonas of claim 16 wherein the yield of muconic acid produced from xylose and glucose is greater than 90% of the maximum theoretical yield.
18. (New) The genetically modified Pseudomonas of claim 6 wherein the xylose and glucose metabolized to muconic acid are derived from lignocellulose.
19. (New) The genetically modified Pseudomonas of claim 6 wherein the Pseudomonas is Pseudomonas putida KT2440.
20. (New) The genetically modified Pseudomonas of claim 6 wherein the Pseudomonas is LC224.
21. (New) A method for making muconic acid comprising the step of contacting a mixture of xylose and glucose with a genetically modified Pseudomonas wherein the Pseudomonas comprises a heterologous D-xylose isomerase pathway comprising xylA encoding for D-xylose isomerase, xylB encoding for xylulokinase and xylE encoding for a D-xylose:H+symporter.
22. (New) The method of claim 21 wherein the xylA, xylB and xylE are from E. coli and wherein the xylE gene comprises mutations resulting in A62V and A455V mutations in the expressed D-xylose:H+symporter.
23. (New) The method of claim 22 wherein the genetically modified Pseudomonas further comprises overexpression of a gene encoding for a major facilitator superfamily transporter and overexpression of an aroB gene encoding for 3-dehydroquinate synthase.
24. (New) The method of claim 23 wherein the genetically modified Pseudomonas produces greater than 33 g/L of muconic acid.
25. (New) The method of claim 23 wherein the genetically modified Pseudomonas produces muconic acid at a rate of greater than 0.17 g/L/h and at a molar yield of greater than 45% from xylose and glucose.
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).
MPEP § 2163 further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.”
“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.
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.
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 factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
The instant specification teaches: A genetically modified Pseudomonas comprising a heterologous D-xylose isomerase pathway wherein the Pseudomonas metabolizes glucose and xylose to produce muconic acid, wherein the heterologous D- xylose isomerase pathway comprises xylA encoding for D-xylose isomerase, xylB encoding for xylulokinase and xylE encoding for a D-xylose:H+symporter, wherein the xylE gene is from E. coli and comprises mutations resulting in A62V and A455V mutations of SEQ ID NO: ? in the expressed D- xylose:H+symporter.
No information, beyond the characterization of a single species: as not above, has been provided by the applicants’, which would indicate that they had possession of the claimed genus of any genetically modified Pseudomonas comprising a heterologous D-xylose isomerase pathway wherein the Pseudomonas metabolizes glucose and xylose to produce muconic acid or the method thereof.
The genus of genetically modified Pseudomonas 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 genetically modified Pseudomonas is adequately described by the disclosure of the structures of the proposed specific genetic modifications of Pseudomonas resulting in A62V and A455V mutations of SEQ ID NO: ? in the expressed D- xylose:H+symporter, with specific polypeptide structure having the associated function/activity. However, that is not the case as no specific polypeptide sequence have been described in the instant specification to the associated with the claimed A62V and A455V mutations; nor the numerous proposed modifications encompassed by 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.
As the claimed genera of genetically modified Pseudomonas comprising a heterologous D-xylose isomerase pathway wherein the Pseudomonas metabolizes glucose and xylose to produce muconic acid (and the method thereof) having widely variable structures and associated function, since minor changes in structure may result in changes affecting function and no additional information (species/variant/mutant) correlating structure with function has been provided. Furthermore, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features” (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895).
Therefore, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Applicants are referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
7. Claim Rejections - 35 USC § 112 (second paragraph)
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 1-10 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.
Claims 9 & 22 recite (see below) – specific mutations with no corresponding sequence identification number. The claims are indefinite without a relatable sequence. Addition of a specific sequence along with A62V and A455V mutations will remedy the indefiniteness.
9. (New) The genetically modified Pseudomonas of claim 8 wherein the xylE gene is from E. coli and comprises mutations resulting in A62V and A455V mutations in the expressed D- xylose:H+symporter.
22. (New) The method of claim 21 wherein the xylA, xylB and xylE are from E. coli and wherein the xylE gene comprises mutations resulting in A62V and A455V mutations in the expressed D-xylose:H+symporter.
Claims 23-25 are included in the rejection for failing to correct the defect present in the base claim(s).
8. Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 6-7, 19 & 21 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Sarkar et al. [Process Biochemistry Volume 102, March 2021, Pages 190-198], Isabel Bator et al. [Front Bioeng. Biotechnol. 2020 Jan 17;7:480], and Bentley at el. Metabolic Engineering Volume 59, May 2020, Pages 64-75.
Sarkar et al. teaches heterologous expression of xylose specific transporter improves xylose utilization by recombinant Zymomonas mobilis bacterial strain in presence of glucose
Construction & screening of xylose specific transporters in evolved Z. mobilis AD50.
Specific glucose & xylose utilization rate (g g−1 h−1): 2.49 & 2.04, respectively.
Directed metabolic engineering has also been coupled with adaptive laboratory evolution (ALE) for isolation of mutant strains that could co-utilize glucose and xylose with comparable efficiency. Although, coherent use of ALE in combination with directed metabolic engineering manifested into development of efficient xylose utilizing Z. mobilis strain, a major challenge that has persisted, is the lower rate of xylose utilization as compared to glucose present in a dual sugar mixture, leading to extended fermentation time and in turn, lower productivity. See introduction, See abstract and the entire article..
The study entails the development of an efficient Z. mobilis strain, which can metabolize glucose and xylose with equal efficacy towards production of ethanol with improved productivity. We constructed an array of xylose specific transporter genes from E. coli, under the influence of two different native Z. mobilis promoters. The xylose transporter genes included an H+ symporter (XylE), a mutant form of the H+ symporter developed through site-directed mutagenesis (XylE*) and a xylose specific ATP Binding Cassette (ABC) type transporter system (XylFGH). Interestingly, the present study is the first to engineer and report the effect of a mutant form of XylE and ABC-type xylose transporter XylFGH in Z. mobilis, under the control of different native Z. mobilis promoters of variable strengths. Previously, we reported an efficient xylose metabolizing Z. mobilis strain using adaptive laboratory evolution strategy, designated as AD50. In the present study, AD50 was used as a host for introducing the xylose specific transporter genes to accomplish co-utilization of xylose and glucose as a desired phenotypic outcome. We screened the efficacy of the xylose specific transporters based on the rate of xylose uptake and extent of xylose consumption by the recombinant Z. mobilis strains, specifically in presence of glucose in dual sugar mixture. Finally, the performance of the selected strain (exhibiting best phenotypic response), with respect to uptake rate of sugars, ethanol titer, yield and productivity, was evaluated in scale up conditions in a bioreactor. The key findings of this study demonstrate that the expression of xylose specific transporters enhances the rate and extent of xylose uptake by the engineered strains in dual sugar supplemented medium coupled with enhanced ethanol productivity.
The reference does not teach using pseudomonas to metabolizes glucose and xylose to produce muconic acid.
Isabel Bator et al. focuses on Pseudomonas putida KT2440 as a well-established chassis in industrial biotechnology. To increase the substrate spectrum, Isabel Bator et al. implemented three alternative xylose utilization pathways, namely the Isomerase, Weimberg, and Dahms pathways. The synthetic operons contain genes from Escherichia coli and Pseudomonas taiwanensis. For isolating the Dahms pathway in P. putida KT2440 two genes (PP_2836 and PP_4283), encoding an endogenous enzyme of the Weimberg pathway and a regulator for glycolaldehyde degradation, were deleted. Before and after adaptive laboratory evolution, these strains were characterized in terms of growth and synthesis of mono-rhamnolipids and pyocyanin. The engineered strain using the Weimberg pathway reached the highest maximal growth rate of 0.30 h−1. After adaptive laboratory evolution the lag phase was reduced significantly. The highest titers of 720 mg L−1 mono-rhamnolipids and 30 mg L−1 pyocyanin were reached by the evolved strain using the Weimberg or an engineered strain using the Isomerase pathway, respectively. The different stoichiometries of the three xylose utilization pathways may allow engineering of tailored chassis for valuable bioproduct synthesis. See abstract and the entire article.
While teaching the use of Pseudomonas putida KT2440 and Isomerase pathway as a means of producing valuable bioproducts, the Isabel Bator et al. do not teach specific or otherwise genetic modifications of Pseudomonas for the production of muconic acid.
Bentley et al. teach the engineering glucose metabolism for enhanced muconic acid production in Pseudomonas putida KT2440. Pseudomonas putida KT2440 has received increasing attention as an important biocatalyst for the conversion of diverse carbon sources to multiple products, including the olefinic diacid, cis,cis-muconic acid (muconate). P. putida has been previously engineered to produce muconate from glucose. Bentley et al. provide strategies enabled enhanced muconic acid production and may also improve production of other target molecules from glucose in P. putida. See abstract and the entire article.
Bentley et al. do not teach specific or otherwise genetic modifications of Pseudomonas for the production of muconic acid.
Based upon the combined teachings of Sarkar et al., Isabel Bator et al. and Bently it would have been obvious before the effective filing date of the claimed invention for one of ordinary skill in the art of enzymology/biotechnology to develop a genetically modified Pseudomonas instead of Zymomonas mobilis of Sarkar et al. (which is a substitution of one bacterial species for another) comprising a heterologous D-xylose isomerase pathway wherein the Pseudomonas metabolizes glucose and xylose to produce muconic acid, wherein the heterologous D- xylose isomerase pathway comprises xylA encoding for D-xylose isomerase, xylB encoding for xylulokinase and xylE encoding for a D-xylose:H+symporter; or a method for making muconic acid comprising the step of contacting a mixture of xylose and glucose (Sarkar et al.) with a genetically modified Pseudomonas wherein the Pseudomonas comprises a heterologous D-xylose isomerase pathway comprising xylA encoding for D-xylose isomerase, xylB encoding for xylulokinase and xylE encoding for a D-xylose:H+symporter, and do so with a reasonable expectation of success.
One of ordinary skill in the art would have been motivated to combine the teachings of the cited art in view of the importance of Pseudomonas putida KT2440 and Isomerase pathway as a means of producing valuable bioproducts (Isabel Bator et al.), such as muconic acid by co-utilization of xylose and glucose (Sarkar et al.), as well as by tapping the teachings Bentley et al. in using Pseudomonas putida KT2440 as an important biocatalyst for the conversion of diverse carbon sources to multiple products, including cis,cis-muconic acid (muconate).
Thus, the claimed invention was within the ordinary skill in the art to make and use at the time was made and was as a whole, prima facie obvious.
9. No claim is allowed.
10. 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