CTNF 18/379,752 CTNF 79002 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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. 07-21-aia AIA Claim (s) 56, 59, and 65-69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bay, S., et al. "Induction of a melanoma ‐ specific antibody response by a monovalent, but not a divalent, synthetic GM2 neoglycopeptide." ChemMedChem: Chemistry Enabling Drug Discovery 4.4 (2009): 582-587 (Bay) . Claims 56, 59, and 65-69 are drawn to a method of producing an antibody to a carbohydrate antigen, the method comprising: (a) immunizing a mammal, except for a human, with a composition comprising a carbohydrate structure; and (b) isolating an antibody that binds to the carbohydrate structure from the mammal or from a hybridoma made using a cell from the mammal, wherein the carbohydrate structure has the formula [(A) - (P)y - (L)z ]x – M. Bay teaches that GM2 is a ganglioside consisting of a sialylated tetrasaccharide [GalNAc b -4((NeuAc a -3)Gal b -4Glc] linked to a ceramide tail (page 582). Bay teaches that it is well established that this GM2 antigen is overexpressed in various types of cancer , including breast, ovary, prostate, small cell lung cancer and melanoma. GM2 was first identified as a target for immunotherapy when tumor regression was observed in melanoma patients after passive immunotherapy with GM2-specific monoclonal antibodies (mAbs) . Furthermore, GM2-induced antibodies (Abs) have been shown to mediate complement-dependent cytotoxicity (CDC) for human GM2+ tumor cells . Finally, the level of serum IgM Abs recognizing the GM2 ganglioside was correlated with an improved survival of stage III melanoma patients. Bay teaches the synthesis of GM2–peptide conjugates using the Huisgen cycloaddition, as well as their immunological evaluation. Bay showed that bacteria-produced GM2 together with the click chemistry provide an efficient route to pure synthetic glycopeptide vaccines that can induce immune responses specific for human tumor cells. As carbohydrates are poorly immunogenic, Bay designed an immunogen capable of eliciting antibodies specific for the tetrasaccharidic portion of the GM2 ganglioside by incorporating aCD4+ Tcell epitope peptide from the VP1 protein of poliovirus type 1 (PV103–115, KLFAVWKITYKDT) (page 583). Two carbohydrate–peptide conjugates were synthesized including one (GM2-tz-PV, 4 ) or two ((GM2-tz)2-PV, 5 ) copies of the GM2 tetrasaccharide at the N terminus of the PV CD4+ Tcell peptide (Scheme 1). PNG media_image1.png 544 678 media_image1.png Greyscale Bay teaches that the immunogenicity of the GM2 glycopeptides was assessed in BALB/c mice (pate 587). Mice were immunized (i.p.) every three weeks with 4 , 5 and 6 in alum supplemented with CpG1826 oligonucleotide (10 mg) (Pro ligo). One week after immunization, sera were collected and tested for IgM and IgG antibodies by ELISA using asialo-GM1, asialo-GM2, GM1 and GM2 gangliosides purified from bovine brain (Sigma) and coated in MeOH at 0.5 mg. Serial dilutions of sera were performed and bound antibodies were revealed using goat anti-mouse IgG peroxidase conjugate (Sigma) and o-phenyldiamine/H 2 O 2 substrate. Bay showed that a fully synthetic glyco-peptide, which is based on a ganglioside carbohydrate moiety, can induce human tumor cell-specific antibodies after immunization in mice (Abstract). Interestingly, the monovalent , but not the divalent, form of GM2 peptide construct induced antimelanoma antibodies . Unlike traditional vaccines, this vaccine is a pure chemically-defined entity, a key quality for consistent studies and safe clinical evaluation. Therefore, such carbohydrate–peptide conjugate represents a promising cancer vaccine strategy for active immunotherapy targeting gangliosides. Thus, Bay teaches a method of producing an antibody to a carbohydrate antigen, the method comprising (a) immunizing a mouse with glyco-peptide 4 . Glyco-peptide 4 is embraced the formula [(A) - (P) y - (L) z ] x - M wherein A is GM2 (e.g., a carbohydrate antigen, or any portion thereof); P is a triazine wherein y is 1, PNG media_image2.png 49 45 media_image2.png Greyscale (e.g., a ring that is not C6-C10 aryl); L is –(CH 2 ) 5 C(=O)NH- wherein z is 1 (e.g., a linker; x is 1; and M is a peptide (e.g., a core, wherein M is not KLH). Bay differs from the instantly claimed invention in that Bay does not explicitly teach a method further comprising (b) isolating an antibody that bids to the carbohydrate structure from the mammal or from a hybridoma made using a cell from a mammal; however, this deficiency would have been obvious. In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983). It would have been prima facie obvious to isolate the antimelanoma antibodies of Bay. One would have been motivated to do so in order to employ the antibodies in the treatment of melanoma. One would have had a reason expectation of success as the antibodies possess antimelanoma properties. Thus, claims 56, 59, and 65-69 would have been obvious based upon the preponderance of evidence . 07-22-aia AIA Claim (s) 57-58, 71, and 73-77 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bay, S., et al. "Induction of a melanoma ‐ specific antibody response by a monovalent, but not a divalent, synthetic GM2 neoglycopeptide." ChemMedChem: Chemistry Enabling Drug Discovery 4.4 (2009): 582-587 (Bay) as applied to claim s 56, 59, and 65-69 above, and further in view of Tsuchiya et al. US 8,008,076 B2 (Tsuchiya) . Claims 57-58, 71, and 73-77 are drawn to a method for producing a nucleic acid encoding an antibody to a carbohydrate antigen, the method comprising (a) immunizing a mammal, except for a human, with a composition comprising a carbohydrate structure; and (b) isolating a cell from the mammal of step (a) that expresses an antibody to the carbohydrate antigen; and (c) isolating a nucleic acid from the cell of step (b) that encodes the antibody to the carbohydrate antigen wherein the carbohydrate structure has the formula [(A) - (P)v - (L)z ]x – M. Bay differs from the instantly claimed invention in that Bay does not teach or reasonably suggest a method comprising (c) isolating a nucleic acid from the cell of step (b) that encodes the antibody to the carbohydrate antigen; however, this deficiency would have been obvious in view of the teachings of Tsuchiya. In the instant case, the references may be combined to show obviousness because Bay and Tsuchiya are each drawn to methods for producing antibodies and/or antibody-encoding nucleic acids from antibody-producing cells. They are from the same field of endeavor, and/or are reasonably pertinent to a method for producing a nucleic acid encoding an antibody to a carbohydrate antigen. An objective of Tsuchiya is to facilitate the acquisition of antibody-producing cells that are infiltrating virus infected cells, cancer cells, abnormal cells forming a benign hyperplasia, and the like, and to improve the efficiency of the production of antibodies as well as nucleic acids encoding them from the antibody-producing cells (Abstract). Tsuchiya discovered that, when cancer tissues comprising infiltrating lymphocytes are transplanted into highly immunodeficient animals that do not have T cells, B cells, and NK cells and further exhibit a low IFN production ability, the differentiation and proliferation of infiltrating lymphocytes are unexpectedly promoted, and the number of plasma cells that produce antibodies recognizing cancer tissues increases dramatically, plasma cells can be separated easily, and antibodies or nucleic acids encoding them can be easily prepared from the plasma cells . Tsuchiya relates to the acquisition of antibody-producing cells (column 1, lines 16-20). Moreover, Tsuchiya relates to methods for producing antibodies and antibody-encoding nucleic acids from these antibody-producing cells. Tsuchiya teaches that, although attempts have been made to separate plasma cells that infiltrate cancer tissues and to continuously produce specific antibodies from those cells, these attempts have failed so far (column 1, lines 46-67). Reasons for the failure include the inability to secure tumor-specific plasma cells (B lymphocytes) in sufficient numbers because of the difficulty of separating them from cancer tissues, and even if separation were successful to some extent, the instability of antibody production with methods that use EBV or hybridomas for immortalizing antibody producing cells. Tsuchiya teaches that, on the other hand, recombinant DNA technologies for creating antibodies having antigen-binding activities similar to those from cloned antibody-producing cells, namely methods for cloning antibody genes and preparing recombinant antibody proteins, are being established . Antibody genes such as Fv, ScFv, Fab, IgG, or IgM can be produced by cloning genes encoding the variable regions of antibody genes. ScFv, which is the smallest recombinant antibody molecule, has a structure in which a heavy chain variable region and a light chain variable region are joined by a linker. An objective of Tsuchiya is to facilitate the acquisition of antibody-producing cells infiltrating lesion tissues formed by abnormal cells (such as virus-infected cells, cancer cells, and abnormal cells forming benign hyperplasia) (column 3, lines 5-20). An objective of Tsuchiya is to provide methods for producing antibodies from antibody-producing cells infiltrating lesion tissues, and nucleic acids encoding these anti bodies . Tsuchiya provides a method of producing nucleic acids encoding antibodies or portions thereof (column 10, lines 18-37). Tsuchiya teaches that plasma cells can be advantageously proliferated at a site of transplantation by transplanting lesion tissues infiltrated with lymphocytes into highly immunodeficient animals. Since such plasma cells that proliferated at a site of transplantation have an ability to produce antibodies against abnormal cells included in the lesion tissues, plasma cells recovered from the site of transplantation are a preferable cloning source of nucleic acids encoding antibodies against abnormal cells, or portions of these nucleic acids. In short, the method of Tsuchiya for producing a nucleic acid encoding an antibody comprises the steps of: (a) transplanting a lesion tissue comprising infiltrating lymphocytes into a highly immunodeficient non-human animal; (b) detecting the proliferation of plasma cells at the site of transplantation; (c) recovering the lesion tissue comprising plasma cells from the site of transplantation; and (d) recovering the nucleic acid encoding the antibody from the recovered lesion tissue . In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983). It would have been obvious to isolate nucleic acid from a cell from a mammal that expresses an antibody to GM2 of Bay. One would have been motivated to do so because Tsuchiya teaches that although attempts have been made to separate plasma cells that infiltrate cancer tissues and to continuously produce specific antibodies from those cells, these attempts have failed so far. One would have had a reasonable expectation of success as Tsuchiya teaches a method for producing a nucleic acid encoding an antibody comprises the steps of: (a) transplanting a lesion tissue comprising infiltrating lymphocytes into a highly immunodeficient non-human animal; (b) detecting the proliferation of plasma cells at the site of transplantation; (c) recovering the lesion tissue comprising plasma cells from the site of transplantation; and (d) recovering the nucleic acid encoding the antibody from the recovered lesion tissue. All of the instant limitations are taught by the combination of Bay and Tsuchiya. A person of ordinary skill in the art would have had a reason to combine the teachings of Bay and Tsuchiya. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Bay and Tsuchiya. Thus, claims 57-58, 71, and 73-77 would have been obvious based on the preponderance of the evidence . Conclusion 12-151-07 AIA 07-97 12-51-07 Claim s 56-59 and 64-78 are pending. Claims 56-59, 65-69, 71, and 73-77 are rejected. Claims 64, 70, 72, and 78 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. No claims are allowed. Contacts Any inquiry concerning this communication or earlier communications from the examiner should be directed to PATRICK T LEWIS whose telephone number is (571)272- 0655. The examiner can normally be reached Monday to Friday, 10 AM to 4 PM EST (Maxi Flex). 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, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /PATRICK T LEWIS/Primary Examiner, Art Unit 1691 /PL/ Application/Control Number: 18/379,752 Page 2 Art Unit: 1691 Application/Control Number: 18/379,752 Page 3 Art Unit: 1691 Application/Control Number: 18/379,752 Page 4 Art Unit: 1691 Application/Control Number: 18/379,752 Page 5 Art Unit: 1691 Application/Control Number: 18/379,752 Page 6 Art Unit: 1691 Application/Control Number: 18/379,752 Page 7 Art Unit: 1691 Application/Control Number: 18/379,752 Page 8 Art Unit: 1691 Application/Control Number: 18/379,752 Page 9 Art Unit: 1691 Application/Control Number: 18/379,752 Page 10 Art Unit: 1691 Application/Control Number: 18/379,752 Page 11 Art Unit: 1691