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 .
Status of the Claims
The preliminary amendment filed 03/14/2024 is acknowledged. Claims 1-6 are canceled and claims 7-21 are new. No restriction is being imposed in this case. Claims 7-21 are under examination.
Sequence Rules
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). The instant application is not in compliance with the sequence rules, particularly 37 CFR. 1.821(d), which requires that reference be made to a particular sequence identifier (SEQ ID NO: X) in the specification and claims at each disclosure of a sequence encompassed by the definitions set forth in 37 CFR 1.821(a)(1) and (a)(2). See also MPEP 2422.04 which states, “[i]t should be noted, though, that when a sequence is presented in a drawing, regardless of the format or the manner of presentation of that sequence in the drawing, the sequence must still be included in the Sequence Listing and the sequence identifier (“SEQ ID NO: X”) must be used, either in the drawing or in the Brief Description of the Drawings.” Specifically, Figure 1 contains an amino acid sequence without any corresponding sequence identifiers. Appropriate correction is required.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 365(c) and foreign priority is acknowledged. Based on the information given by Applicant and an inspection of the prior applications, the examiner has concluded that the subject matter defined in the instant claims is supported by the disclosure in PCT/EP2021/086853. Further, the certified copy of the foreign priority application provides support in the manner of 112(a). Therefore, the effective filing date of the instant application is 12/23/2020.
Claim Interpretation
The term “huLAG-3 VHH” in the claims is interpreted encompassing a human single domain antibody that targets lymphocyte-activation gene 3 (abbreviated as LAG-3; also known as CD223).
While claims 19-21 encompass the mental step of “diagnosing” in the alternative, administering the recited huLAG-3 was not routine in the art at the time of the filing of the invention.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: ANTI-LAG-3 SINGLE DOMAIN ANTIBODIES AND METHODS THERFOR.
Claim Objections
Claims 10 and 11 are objected to because of the following informalities. Claims 10 and 11 recite “the four FR sequences are each have at least...”, which is grammatically awkward. The “are” is unnecessary and should be deleted from the claims. Appropriate correction is required.
Claims 15 and 17 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112(b)
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 19-21 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.
(i) Claims 19-21 recite “a disease and disorder”, which is confusing since the two terms are not necessarily the same. While there can be overlap between a disease that has an identifiable cause and a disorder resulting in functional disruption that has multiple contributing factors, the two terms may also be non-overlapping. It is suggested the phrase be amended to recite “disease or disorder”.
(ii) Claim 21 recites the disease/disorder is chosen from “cancers and tumors” followed by a list of specific types of cancers and tumors, and thus reads upon an exemplary list of different cancer and tumor types. Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claims. See MPEP 21734.05(d). In addition, the list of diseases is a Markush grouping. A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group “consisting of” (rather than “comprising” or “including”) the alternative members (Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196). See MPEP 2173.05(h), which provides guidance on acceptable Markush language, noting that alternatives may be set forth as “a material selected from the group consisting of A, B, and C” or “wherein the material is A, B, or C”. Note that these issues could be addressed by amending the clause to recite, “wherein the disease or disorder is advanced and/or metastatic solid tumors, non-small-lung cancer, glioblastoma, melanoma, breast cancer, haematological cancer, head-and-neck cancer, liver cancer gastric cancer, oesophageal cancer or colon cancer”.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 7-14, 16 and 18-21 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims are drawn to huLAG-3 VHH (single domain antibodies) consisting of four framework region (FR) sequences and three complementarity determining region (CDR) sequences, wherein at least one of the CDR sequences has at least an 80% or 99% sequence identity with any one of SEQ ID NOs: 1-48. Claims 7, 8, 10-12 and 18-21 encompass three CDRs selected from SEQ ID NOs: 1-48 without any regard to whether the resulting VHH comprises a CDR1, CDR2 and CDR3 sequence, and therefore result in over 17,000 combinations VHH molecules not disclosed in the instant application. Further, claims 18-21 require the huLAG-3 VHH molecules have either pharmaceutical or diagnostic functions or both.
The CDR1 sequences are set forth in SEQ ID NOs: 1-16, CDR2 sequences are set forth in SEQ ID NOs: 17-32 and CDR3 sequences are set forth in SEQ ID NOs: 33-48. While claims 9 and 13 encompass VHH molecules with three CDRs selected from one of each of these groups, nevertheless, these still represent mix and match CDR selection resulting in over 4,000 VHH molecules not disclosed in the instant application. Regarding the four framework sequences, FR1, FR2, FR3 and FR4, claims 10-14 and 16 encompass framework regions, although claims 10-13 also take a mix and match approach to framework selection. Claims 14 and 16 each recite sequences encompassing the entire huLAG-3 VHH (i.e., SEQ ID NOs: 113-128), however, they require only 80% sequence identity to the recited sequences.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered when analyzing claims for compliance with the written description requirement include: actual reduction to practice; disclosure of drawings or structural chemical formulas; sufficient relevant identifying characteristics (e.g., disclosure of complete or partial structure, physical and/or chemical properties, structure/function correlation); method of making the claimed invention; level of skill and knowledge in the art; and predictability in the art. See MPEP §2163.
With respect to antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
In deciding whether the application complies with the written description requirement of 35 USC 112(a) or 35 USC 112 (pre-AIA ), first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. From the specification, it is clear that Applicant has possession of VHH molecules comprising the sequences set forth in instant SEQ ID NOs: 113-128 (see p. 14, Table 3 of the instant specification). While generically the structure of antibodies is known, the structure of the presently claimed antibodies can vary substantially within the above given claimed recitations. As noted above, claims 7-13 and 18-21 recite a mix and match approach to selecting CDRs and FR regions that result in over 17,000 undisclosed VHH molecules. Further, claims 7, 9, 10, 12-14, 16 and 18-21 encompass only 80% sequence identity to the recited sequences. Therefore, the claims encompass a large genus of possible huLAG-3 VHH molecules.
Regarding antibodies, the prior art teaches that small changes in the amino acid structure of the CDRs can have large effects on activity. For instance, Piche-Nicholas et al. (MAbs. 2018; 10: 81-94. doi: 10.1080/19420862.2017.1389355) teach that the “binding affinity of IgG molecules…to FcRn that differed by only a few amino acid residues in CDRs revealed that small changes in CDRs, as minute as one amino acid residue change, could alter affinity to FcRn up to 79-fold.” See p. 89, right column, last paragraph of Piche-Nicholas et al. Further, while it is recognized that an antibody can be described by its CDRs, the art also teaches that that even a single amino acid substitution in a framework region can result in dramatic changes in activity (see Liang et al., Scientific Reports (2021)11: 22365, especially, paragraph bridging pages 6-7). The specification does not disclose a representative number of species capable of describing the claimed genus of over 17,000 VHH molecules. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). With the exception of SEQ ID NOs: 113-128, the skilled artisan cannot envision the detailed chemical structure of the encompassed VHH molecules, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, only isolated polypeptides comprising the amino acid sequence set forth in SEQ ID NOs: 113-128, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Scope of Enablement
Claims 7-14, 16 and 18-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a huLAG-3 VHH molecule having the sequence set forth in SEQ ID NOs: 113-128, methods of diagnosing a disease/disorder associated with huLAG-3 expression in tissues or cells of a subject comprising administering to said subject a huLAG-3 VHH having the sequence set forth in SEQ ID NOs: 113-128 and a method of treating a subject with cancer comprising administering a huLAG-3 VHH having the sequence set forth in SEQ ID NO: 113 as well as a pharmaceutical composition comprising SEQ ID NO: 113, does not reasonably provide enablement for the claims as broadly recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” (See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 Fed. Cir. 1988). These factors include, but are not limited to: (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The claims are broad with respect to the recited huLAG-3 VHH molecules. The claims recite huLAG-3 VHH (single domain antibodies) consisting of four framework region (FR) sequences and three complementarity determining region (CDR) sequences, wherein at least one of the CDR sequences has at least an 80% or 99% sequence identity with any one of SEQ ID NOs: 1-48. Claims 7, 8, 10-12 and 18-21 encompass three CDRs selected from SEQ ID NOs: 1-48 without any regard to whether the resulting VHH comprises a CDR1, CDR2 and CDR3 sequence, which results in over 17,000 VHH molecules. Claim 18 recites a pharmaceutical composition comprising a huLAG-3 VHH according to claim 7 and claims 19-21 encompass diagnosing or treating diseases/disorders associated with an overexpression of huLAG-3 comprising administering the huLAG-3 VHH according to claim 7. The CDR1 sequences are set forth in SEQ ID NOs: 1-16, CDR2 sequences are set forth in SEQ ID NOs: 17-32 and CDR3 sequences are set forth in SEQ ID NOs: 33-48. While claims 9 and 13 encompass VHH molecules with three CDRs selected from one of each of these groups, they still represent mix and match CDR selection resulting in over 4,000 VHH molecules. Regarding the four framework sequences, FR1, FR2, FR3 and FR4, claims 10-14 and 16 encompass framework regions, although claims 10-13 also take a mix and match approach to framework selection. Claims 14 and 16 each recite sequences encompassing the entire huLAG-3 VHH (i.e., SEQ ID NOs: 113-128), however, they require only 80% sequence identity to the recited sequences.
The instant specification discloses that radiolabeled mouse LAG-3 VHH molecules (moLAG-3) “positively correlate[d] with the percentage of LAG-3+ tumor-infiltrating immune cells in different tumor models” (see p. 21, lines 14-32, Figure 1). Further, treatment of a mouse model with PD-1 inhibitors resulted in “upregulation of mouse LAG-3 on MC38 tumor-infiltrating immune cells but not in immunological organs” (see pages 21-22, Figures 2-3). In addition, a moLAG-3 antibody increased the “antitumor activity” of PD-1 inhibition in a mouse model (see pages 22-23, Figure 4). These studies provide evidence in a mouse model that the moLAG-3 antibody may be useful as a cotreatment in cancer therapy.
The specification discloses the development of specific human LAG-3 VHH molecules (see p. 23, Figures 5-6), which were tested in vitro for their ability to block human LAG-3 interaction with HLA-DR (its ligand) and for therapeutic efficiency. The huLAG-3 VHH molecules denoted as 3150 (SEQ ID NO: 113), 3185 (SEQ ID NO: 125), 3187 (SEQ ID NO: 119) and 3194 (SEQ ID NO: 126) were capable of blocking huLAG-3/HLA-DR binding (see p. 24, Figure 7B), although only 3150 was capable of activating huLAG-3+ 2D3 cells (see p. 24, Figure 7D). This 2D3 cell-based assay is described in Versteven et al. (Oncotarget, 2018, Vol. 9, (No. 45), pp: 27797-27808—on IDS filed 12/22/2023). The specification concludes that “[t]he ability of VHHs to block the interaction of human LAG-3 and its canonical ligand HLA-DR is not predictive for their therapeutic efficacy”, thus providing evidence that Nb 3150 (SEQ ID NO: 113) has potential benefit in cancer co-treatment. Claims 7-13 and 18-21 recite a mix and match approach to selecting CDRs and FR regions. Further, claims 7, 9, 10, 12-14, 16 and 18-21 encompass only 80% sequence identity to the recited sequences. Therefore, the claims encompass many possible huLAG-3 VHH molecules while the evidence only shows that a limited number have the required binding and activation capability. In addition to treatment, claims 19-21 encompass diagnosis comprising administering a huLAG-3 according to claim 7. Nevertheless, the claims provide no steps as to how to diagnose disease using the claimed huLAG-3 VHH molecules. Therefore, the evidence provided in the instant specification is not commensurate with the breadth of the claims.
The number of mutations generally possible in any given protein that can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g., such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. Regarding antibodies, the art teaches that small changes in the amino acid structure of the CDRs can have large effects on activity. For instance, Piche-Nicholas et al. (cited above) teach that the “binding affinity of IgG Molecules…to FcRn that differed by only a few amino acid residues in CDRs revealed that small changes in CDRs, as minute as one amino acid residue change, could alter affinity to FcRn up to 79-fold.” See p. 89, right column, last paragraph of Piche-Nicholas et al. Further, while it is recognized that an antibody can be described by its CDRs, the art also teaches that that even a single amino acid substitution in a framework region can result in dramatic changes in activity (see Liang et al., cited above; especially, paragraph bridging pages 6-7).
Although machine learning algorithms have improved the ability to predict protein 3D structure from sequences, methods based on artificial intelligence for predicting the impact of mutations on protein stability still face challenges, including prediction biases towards “generalization”, “data set”, “destabilizing mutations” and the inability to predict the effects of multiple mutations. See Figure 1, at p. 162 and the discussion at pages 165-166 of Pucci et al. (Current Opinion in Structural Biology 2022, 72: 161-168). Even in the case of single mutations, artificial intelligence programs do not accurately “predict the impact of mutation on protein stability” or function (see p. 2, 2nd paragraph and p. 7, 1st full paragraph of Pak et al., PLoS ONE 18(3): e0282689. https://doi.org/10.1371/journal.pone.0282689). In the instant case, the claims encompass VHH molecules with up to a 20% divergence from the recited sequences. Applicants have provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions which are tolerant to change by amino acid substitutions or deletions, and the nature and extent of changes that can be made in these positions. Although the specification outlines art-recognized procedures for producing and screening for active VHH molecules, this is not adequate guidance as to the nature of active derivatives that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation.
Due to the large quantity of experimentation necessary to test the extremely large genus of VHH molecules for the ability to bind LAG-3 as well as diagnose and treat disease, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the unpredictability of the effects of mutation on protein structure and function, and the breadth of the claims which fail to recite limitations on the VHH molecules, the diseases treated and how to diagnose said diseases, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Closest Prior Art
Lecocq et al. (Biomolecules 2019, 9, 548; doi:10.3390/biom9100548—on IDS filed 12/22/2023) disclose a number of mouse LAG-3 VHH molecules (see particularly, p. 7, Figure 1, Nbs 3132, 3134, 3141, 3204,3206,3208, 3209, 3210 and 3366). Nevertheless, the instant claims recite a huLAG-3 VHH, which is not reasonably construed to read upon the mouse LAG-3 VHH molecules disclosed in Lecocq et al. Moreover, Lecocq et al. do not disclose the sequences of the mouse LAG-3 VHH molecules. In addition, some prior art antibodies and single domain antibodies share 80-88% sequence similarity with some of the instantly claimed huLAG-3 VHH sequences, however, the prior art references do not teach that these antibodies can bind to LAG-3. For instance, Deschaght et al. (Front. Immunol. 8:420-420(2017)) teach a human recepteur d’origine nantais (RON) receptor kinase nanobody that shares about 86% sequence identity with instant SEQ ID NO: 122:
Query Match 85.8%; Score 556; Length 127;
Best Local Similarity 86.6%;
Matches 110; Conservative 1; Mismatches 10; Indels 6; Gaps 1;
Qy 1 QVQLQESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREGVSCISSSDGSTYY 60
:||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREGVSCISSSDGSTYY 60
Qy 61 ADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCATDRYGTCTG------PYDNWGQG 114
||||||||||||||||||||||||||||||||||||||| | | ||||
Db 61 ADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCATDLKRRCRDYARPQRGNDYWGQG 120
Qy 115 TQVTVSS 121
|||||||
Db 121 TQVTVSS 127
Nevertheless, there is no suggestion that RON has any relation to LAG-3. Similarly, Steyaert et al. (US20170183404) discloses a nanobdy to the µ-opioid receptor (MOR1) that shares about 88% sequence identity with instant SEQ ID NO: 119:
Query Match 86.7%; Score 557.5; Length 150;
Best Local Similarity 88.7%;
Matches 110; Conservative 2; Mismatches 9; Indels 3; Gaps 1;
Qy 1 QVQLVESGGGLVQAGESLRLSCAASGFTFDDYAIGWFRQAPGKEREGVSCISSSDGSTYY 60
||||||||||||||| |||||||||||||||||| |||||||||||||||||||||||||
Db 1 QVQLVESGGGLVQAGGSLRLSCAASGFTFDDYAIA WFRQAPGKEREGVSCISSSDGSTYY 60
Qy 61 ADSVKGRFTISSDNAENTVYLQMNSLKPEDTAVYYCAADRYRDCRGPYDY---WGQGTQV 117
|||||||||||:|||:||||||||||||||||||||||| | | | | |||||||
Db 61 ADSVKGRFTISNDNAKNTVYLQMNSLKPEDTAVYYCAADLSRSCGRGYRYLEVWGQGTQV 120
Qy 118 TVSS 121
||||
Db 121 TVSS 124
Again, however, MOR1 is not LAG-3.
Conclusion
Claims 7-14, 16 and 18-21 are rejected and claims 15 and 17 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M BORGEEST whose telephone number is (571)272-4482. The examiner can normally be reached M-F 9-5:30 EDT.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675