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 .
Claims 1,11,33,35,44,75-84 are under examination.
Claim Rejections - 35 USC § 112
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 1,11,33,35,44,75-84 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. Claim 1 mentions a targeted delivery of a payload to a target cell.
Claim 1 recites “transfecting one or more cells with a lipid-based particle comprising an RNA encoding a bispecific peptide or polypeptide comprising a first binding moiety and a third binding moiety” and “the first binding moiety is displayed on the surface of the target cell.” It is unclear if the target cell is from the transfected cell population or another cell population because both the transfected cell/s and the target cell are able to secrete or display the first binding moiety. It is not clear if the first binding moiety is expressed by the target cell and is used by the target cell to bind to the payload or if the first binding moiety merely attaches to the target cell. The claim does mention a third binding moiety produced by one or more transfected cells but does not clarify what the third binding moiety will bind to. The independent and dependent claims fail to provide additional clarification concerning how the target cell interacts with the transfected cells and/or the payload. For purposes of examination, the examiner will assume that the bispecific polypeptide/peptide moieties are capable of binding to both a moiety attached to a payload (2nd binding moiety) and to a moiety on the target cell.
Claim 35 is problematic because independent claim 1 recites that RNA in a lipid-based particle is transfected into cells that are then able to express and secrete a bispecific peptide or polypeptide comprising the first and third binding moieties. However, claim 35 only mentions that the RNA is administered, not the transfected cells. It is not clear how cells are able to become transfected when the RNA is administered without first transfecting the cells. Claim 35 also recites, “(ii) the payload which comprises or is linked to the second binding moiety or RNA coding therefor.” This conflicts with independent claim 1 because claim 1 recites that the second binding moiety attaches to the first binding moiety and not the RNA.
The preamble of claim 44 recites “A method for targeted delivery of a payload to target cells in a subject.” The claim recites, “ a lipid based particle comprising an RNA encoding a bispecific peptide or polypeptide comprising a first binding moiety and a third binding moiety; and a therapeutic payload which comprises or is linked to a second binding moiety, wherein the first bind moiety and the second binding moiety bind to each other.” A target cell is not mentioned. The actual claim limitations fail to clarify how the payload is delivered to the target cell.
Claim Rejections - 35 USC § 103
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1,11,33,35,44,75-78,81-82 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang WO 2019027847 in view of Rezvani (WO 2018237300)
Zhang teaches a method for targeted delivery of a payload to a target cell comprising: (i) transfecting one or more cells with a lipid-based particle (liposome) (Paragraphs 7, 89-90 and 99 of Zhang) comprising a RNA (Paragraphs 7,11 and 71 of Zhang) encoding a bispecific polypeptide (Paragraphs 4,6-7,80,89-90, and 106, 128 of Zhang) comprising a first binding moiety and a third binding moiety (Paragraphs 6-8,103-104 of Zhang), (ii) allowing the one or more transfected cells to express and secrete the bispecific polypeptide such that the bispecific polypeptide’s third binding moiety binds to the target cell/a cancer cell (Paragraphs 6-8 of Zhang) and the first binding moiety attaches to a second binding moiety on a therapeutic payload such as an effecter cell/a T cell, a NK cell, CD4+ T cell, CD8+ T cell, CD19+ cell, a CD20+ cell, a macrophage, or a B cell (Paragraphs 6,9,103-104, 241-242 of Zhang), (iii) adding a payload which comprises or is linked to a second binding moiety, wherein the first binding moiety and the second binding moiety are capable of binding to each other (the 2nd binding moiety present on effector cells—Paragraphs 241-242) as in instant Claim 1,81-82. Zhang teaches a method for targeted delivery of a payload to target cells in a subject, comprising administering to the subject : a lipid based particle (Paragraphs 14-15,89-90 and 99) comprising a RNA (Paragraphs 11 and 71) encoding a bispecific polypeptide (Paragraphs 4,7,80,89-90, and 106, 128 of Zhang) comprising a first binding moiety and a third binding moiety (Paragraphs 6-8,20,103-104 of Zhang); and wherein the first binding moiety binds to a second binding moiety attached to an effector cell/payload(Paragraphs 6-8 and 241-242 of Zhang) as in instant Claim 44.
Zhang teaches that effecter cells already present in-vivo can attach to the bispecific polypeptides to attack cancer cells, thus providing a deadly payload in the form of an immune cell (Paragraphs 241-242). The Zhang reference fails to state that effecter cells are administered. However, Rezvani teaches that immune cells such as T cells can be genetically engineered to express chimeric antigen receptors (Paragraph 128 of Rezvani). Rezvani further teaches that such cells can be directly administered to patients (Paragraphs 167-168,181-182 of Rezvani). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have administered T cells with chimeric antigen receptors. An artisan would have been motivated to have engineered such T cells to have chimeric antigen receptors because such cells can be modified to have antigenic specificity to certain cancer antigens, allowing for these cells to attack cancer (Paragraph 128 of Rezvani). Because chimeric antigen receptors help direct T cells to cancer sites, there would be a high expectation for success (Paragraph 128) as in instant Claims 1,44, and 75.
Dependent Claims taught by Zhang
Zhang discloses wherein the first binding moiety and the third binding moiety are linked to each other by a linker (Paragraphs 19-20,110,119, 192,and 200 of Zheng) as in instant Claim 11. Zhang discloses wherein the target cell is present in a subject (Paragraph 245) as in instant Claim 33. Zhang discloses the RNA encoding a bispecific polypeptide comprising the first binding moiety (Paragraphs 6-8,11,71,89-90, and 99); ii the payload which comprises or is linked to the second binding moiety (Paragraphs 6-8) as in instant Claim 35. Zhang discloses wherein the effector cell is a T cell (Paragraphs 8 and 246) as in instant Claim 76. Zhang discloses wherein the target cell is a cancer cell (Paragraphs 9 and 245) as in instant Claim 77. Zhang discloses wherein the second moiety is scFv (Paragraphs 6,25 and 241) as in instant Claim 78.
Zhang teaches delivering RNA that encodes for a bispecific polypeptide. Zhang teaches that such a bispecific polypeptide can successfully bind to immune cells (capable of having a payload) and also target cells (such as cancer cells). The immune cells mentioned in Zhang are already in the body and are not administered into a subject. However, Rezvani teaches that therapeutic T cells (effector/immune cells) can be successfully introduced into the body. Therefore, an artisan would have been motivated to have administered such cells to provide additional therapeutic benefits. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All the clamed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combinations would have yielded predictable results to one of ordinary skill in the art at the time of the invention (See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.s and Ph.D.s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in immunotherapy. Therefore, the level of ordinary skill in the art is high.
Response to Applicants Arguments
Applicants argue the following:
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The instant set of claims do not require the presence of two distinct types of extracellular vesicles, ones that bind to cancers cells and different ones that bind to immune cells. Adding such a limitation to the claim would help distinguish the claimed invention from the prior art.
Applicants further argue that the combination of Zhang and Rezvani in the rejection is not logical because Zhang relies on T cells already present in-vivo not the modified T cells taught by Rezvani. An artisan would have been motivated to have administered genetically modified T cells of Rezvani because they are genetically engineered so that they are primed to better kill cancer cells. Thus, the cells of Rezvani can further improve cancer treatment outcomes.
Applicants further argue that the RNA within the extracellular vesicles in Zhang is not responsible for encoding the antigen binding domains (binding moieties) displayed on the surface of the extracellular vesicle. The manner in which the instant claims are drafted does not necessarily require this. Claim 1 recites “transfecting one or more cells with a lipid-based particle comprising an RNA encoding a bispecific peptide or polypeptide comprising a first bind moiety and a third binding moiety.” Claim 44 recites “a lipid based particle comprising an RNA encoding a bispecific peptide or polypeptide comprising a first binding moiety and a third binding moiety.” Because of the manner in which the claims are drafted, the claims can be interpreted as meaning that a lipid particle comprises the first binding moiety and the third binding moiety. This is a valid interpretation since binding moieties are frequently on lipid particles.
Claims 1,11,33,35,44,75-80 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang WO 2019027847 in view of Rezvani (WO 2018237300), Van Hoecke et al. “mRNA Encoding a Bispecific Single Domain Antibody Construct Protects against Influenza A Virus Infection in Mice” Molecular Therapy: Nucleic Acids, Vol. 20, June 2020, and Frey (WO 2020053239). Van Hoecke is cited in the IDS document dated 3/10/2023.
Zhang and Rezvani apply as above to teach claims 1,11,33,35,44,75-78. Zhang teaches that the second moiety can be connected to a payload/effecter cell; however, Zhang does not teach that the second moiety can be VHH. Van Hoecke teaches that the second binding moiety can be VHH/nanobodies (Page 777, right side). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have used VHH as the second binding moiety. An artisan would have been motivated to have used such a binding moiety because VHH can successfully attach to immune cells by binding to FcγReceptors on the immune cells and VHH is able to bind to other targets such as a first binding moiety discussed in Van Hoecke (Page 777, right side, bottom paragraph). There would have been a high expectation for success because Van Hoecke teaches that VHH can successfully connect to immune cells which carry payloads and also bind to other binding moieties. (Page 777, right side, bottom paragraph of Van Hoecke) as in instant Claim 78.
Neither Zhang nor Van Hoecke teach the specific CDR sequences associated with the VHH domain. However, Frey recognizes that such binding moieties such as VHH can have the following constructs: CDR1 sequence: GVTISALNAMAMG (SEQ ID NO: 15), CDR2 AVSERGNAM (SEQ ID NO: 16), and CDR3 sequence LEDRVDSFHDY (SEQ ID NO: 17) (Paragraph 77 of Frey). It would have been obvious to an artisan of ordinary skill in the art to have included VHH binding moieties with these CDR regions. An artisan would have been motivated to have a VHH with these specific CDR regions because they successfully promote binding of moieties to immune cells (Paragraph 77 of Frey). Furthermore, an artisan would have been motivated for the first binding moiety to be SRLEEELRRRLTE (SEQ ID NO: 14) because it can successfully bind to a VHH moiety (Paragraph 76 of Frey) as in instant claims 78-80.
Dependent Claims taught by Frey
Frey teaches wherein the first binding moiety and the third binding moiety are linked to each other by a linker (Paragraphs 76- 78 of Frey) as in instant Claim 11. Frey teaches wherein the payload is an immune effector T cell comprising a chimeric antigen receptor (Paragraph 213 of Frey) as in instant Claims 75-76.
Zhang teaches delivering RNA that encodes for a bispecific polypeptide. Zhang teaches that such a bispecific polypeptide can successfully bind to immune cells (capable of having a payload) and also target cells (such as cancer cells). The immune cells mentioned in Zhang are already in the body and are not administered into a subject. However, Rezvani teaches that therapeutic T cells (effector/immune cells with payloads) can be successfully introduced into the body. Therefore, an artisan would have been motivated to have administered such cells to provide additional therapeutic benefits. An artisan would have been further motivated to have used VHH as a second moiety because Van Hoecke teaches that it can attach to immune cells and bind to additional targets. Furthermore, Frey teaches the CDR regions/sequences that can be present in a VHH moiety to assist with binding. Frey also teaches that a binding moiety that can successfully bind to the VHH second moiety would comprise a sequence SRLEELRRRLTE (SEQ ID NO: 14) which can be used as a first binding moiety. An artisan would have been motivated to have used VHH, attached to immune cells, as a second moiety in order to guide immune cells to additional targets. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All the clamed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combinations would have yielded predictable results to one of ordinary skill in the art at the time of the invention (See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.s and Ph.D.s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in immunotherapy. Therefore, the level of ordinary skill in the art is high.
Response to Applicants Arguments
Applicants argue that the Frey reference is an inappropriate reference to use in the rejection above because it does not teach binding of VHH to immune cells. Van Hoecke is used to teach that VHH regions can successfully attach to immune cells and also other binding moieties. If a moiety with VHH, second binding moiety, is used, the first binding moiety needs to have a sequence that can successfully bind to it because the first binding moiety and second binding moiety must bind to each other. Frey teaches a sequence, SRLEEELRRRLTE, that is able to successfully bind to the VHH in the second binding moiety. An artisan would have been motivated to have included SRLEEELRRRLTE into the first binding moiety because it can facilitate binding with a moiety that contains VHH. Frey is used to teach moiety binding and not attaching to immune cells.
Claims 1,11,33,35,44,75-78,81-84 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang WO 2019027847 in view of Rezvani (WO 2018237300) and Germeroth BR 112018008081 (dated Nov 13, 2018). Germeroth BR 112018008081(dated 2024-11-19) is used as a translation.
Zhang and Rezvani apply as above to teach claims 1,11,33,35,44,75-78,81-82. Zhang does not specify that the first binding moiety is a peptide tag and the second binding moiety is a tag-binding moiety. However, Germeroth teaches that the first binding moiety can be a peptide tag and the second binding moiety can be a tag binding moiety (Paragraphs 6,13, and 98-103). It would have been obvious to an artisan of ordinary skill in the art to have used the binding moieties taught by Germeroth since Germeroth teaches that a tag-binding moiety can be present on a target cell such as a T cell which can bind to a peptide tag attached to an agent capable of stimulating/affecting cells (Abstract, Paragraphs 6,13, and 98-103 of Germeroth). Because the T cell can be manipulated through the binding of the peptide tag moiety with the tag-binding moiety, there would have been a high expectation for success (Abstract, Paragraphs 6,13, and 98-103 of Germeroth) as in instant Claims 83-84.
Zhang teaches delivering RNA that encodes for a bispecific polypeptide. Zhang teaches that such a bispecific polypeptide can successfully bind to immune cells (capable of having a payload) and also target cells (such as cancer cells). The immune cells mentioned in Zhang are already in the body and are not administered into a subject. However, Rezvani teaches that therapeutic T cells (effector/immune cells) can be successfully introduced into the body. Germeroth teaches that a peptide tag can serve as a first binding moiety and a tag-binding moiety can serve as a second binding moiety because the peptide tag and the tag binding moiety can bind together and effectively stimulate/affect target cells. Therefore, an artisan would have been motivated to have administered such cells to provide additional therapeutic benefits. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All the clamed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combinations would have yielded predictable results to one of ordinary skill in the art at the time of the invention (See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.s and Ph.D.s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in immunotherapy. Therefore, the level of ordinary skill in the art is high.
Conclusion
All claims stand rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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