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 .
Application Status
This action is written in response to applicant’s correspondence received 9 March 2026. Claims 22-23, 52, 54, 92-94, and 114-115 are currently pending. Claims 92-94 and 114-115 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 22-23, 52, and 54 are examined herein. The restriction requirement mailed 27 October 2023 is still deemed proper. Applicant's elected Group I, claims 22-23, 52, 54, and 70-80 without traverse in the reply filed 29 January 2024.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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 22-23, 52, and 54 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.
The term “about the human equivalent of a dose of 1 x 107 cells” in claim 52 is a relative term which renders the claim indefinite. The term “about the human equivalent of a dose of 1 x 107 cells” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear if the claims are intended to be limited to a method of administering about 1 x 107 of the claimed cells to a human subject or if the claims are intended to be limited to an amount of cells that, when administered to a subject, produces a therapeutic benefit equivalent to a therapeutic benefit seen when mice are administered about 1 x 107 of the claimed cells. Further, the size of the human in the claim is undefined and the size of the dose makes reference to the claimed human. Accordingly, the reference to the variable object (i.e., the size of the human) renders the size of the claimed dosage unclear.
Regarding claims 22-23, 52, and 54, as the claims are ultimately dependent on claim 52 and do not rectify the 35 USC 112(b) rejection above, the claims are also rejected under 35 USC 112(b).
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.
Claims 22-23, 52, and 54 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 the intravenous administration to a human subject with MPS I two or more sequential doses of genetically modified B cells to enable synergistic in vivo production of IDUA, FIX, LPI, or LCAT, does not reasonably provide enablement for the claimed synergistic production of the claimed compounds via any administration method as currently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
For the purposes of examination, the claimed limitation of “at least about the human equivalent of a dose of 1 x 107 cells in a mouse” is interpreted as being limited to 1 x 107 cells.
Regarding claim 52, exemplary factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (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. See MPEP 2164.01(a). All of these factors were considered, along with others, and a sufficient number are addressed below so as to create a prima facie case.
Nature of the Invention and Breadth of the Claims
Claim 52 is drawn towards a method for treating MPS 1 in a subject via the administration of two or more sequential doses genetically modified B cells that can express IDUA, FIX, LPI, or LCAT that enables synergistic production of the compounds. For the purposes of this enablement rejection, the analysis will focus on the predictability of enabling the “synergistic production” of the claimed compounds via the administration of two or more of the claimed sequential doses via the use of any administration method. It is noted that the claimed “synergistic production” will be interpreted in this analysis as an effect wherein the amount of compound produced when the two claimed doses are administered is more than the sum of the individual doses separately via any administration method in order to treat MPS I in a subject.
Because the genus of administration methods present in the claim is not limited to a specific administration method, the claims encompass all possible administration methods, including intraperitoneal injection, that can enable the claimed synergistic production.
Accordingly, enablement of the method requires one skilled in the art to be able to produce a synergistic production of the claimed compounds via the administration of two claimed doses, wherein the resulting production of the compounds is more than the sum of the individual doses separately via any administration method.
State of the Art/Unpredictability in the Art
Regarding the state of the art, the art demonstrates that there are many dose-response curves known in the art; however, the art does not teach that the generation of a synergistic response via the administration of two or more doses is predictable or well known.
Ramaiah (Toxicologic Pathology 45.1 (January 2017): 223-237, first published 13 November 2016) is drawn towards a review study concerned with how anatomic and clinical pathology data can be interpreted jointly in order to fully characterize test article-related findings (pg. 223). Ramaiah teaches that well-known dose-response curves include linear responses, threshold responses, J-shaped responses, saturation curves, sigmoid curves, and U- shaped curves (pg. 226; see Figure 1).
Therefore, while Ramaiah teaches that it was well-known in the art that you will get a gradual continuous increase in a response with increasing dosages, Ramaiah does not teach or suggest the generation of a synergistic response (i.e., a response that is greater than the sum of two individual doses) via the administration of two or more doses is predictable or well known.
Thus, in view of the prior art, it is highly unpredictable if or how one skilled in the art could administer the claimed doses to enable a synergistic production of the claimed compounds.
Guidance in the Specification/Prescence of Working Examples
While the specification does provide potential for the synergistic administration of three sets of 1 x 107 genetically modified B cells such that they produce greater serum levels of IDUA when compared to a single dose of 3 x 107 cells in a subject in order to treat MPS I (see Figs. 5-6), the instant specification also teaches that the “synergy across multiple dosages was only [emphasis added] observed in groups of mice that were delivered the engineered B cells intravenously, but not in the mice that received the engineered B cells via intraperitoneal injection” (pg. 71).
Accordingly, in light of the specification, it is highly unpredictable if one skilled in the art could administer the claimed dosages through any administration method in order to generate the synergistic production of the claimed compounds. Because the specification explicitly states that there are administration methods that do not enable the synergistic production of the claimed compounds, it would not have been predictable to perform the method as claimed in light of the teachings of the specification.
Experimentation Required
With regard to the claims, the skill of those in the relative art is high, but still, given the state and unpredictability of the art, undue experimentation would be required to determine if a synergistic production of the claimed compounds is seen with any administration method. For example, large-scale and extensive preclinical testing would be required in order to evaluate if any given administration method could effectively deliver the claimed cells to a subject, much less wherein the administration method resulted in the claimed synergistic production of the compounds. Even for a single administration method, tests in multiple animal models must be performed wherein the evaluation of the biodistribution and amount of compound produced is tested, followed by the long-term analysis of the stability and therapeutic benefits of the claimed synergistic production of the compounds as it relates to the treatment of MPS I. Further, given the great unpredictability in the art regarding the generation of a synergistic production of compounds in general with a given dosage, it is highly unpredictable whether the claimed dosages could enable synergistic production of the claimed compounds in vivo.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples of enabling synergistic production of the claimed compounds, it is the conclusion that undue experimentation would be required to make and use the invention.
Regarding dependent claims 22-23, 54, and 71-72, the claims are dependent on claim 52 and do not rectify the enablement rejection above. Accordingly, claims 22-23, 54, and 71-72 are also rejected under 35 U.S.C. 112(a).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 52 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-12, 15, 57, and 59 of copending Application No. 18/034,865 (reference application) in view of Scholz (PG Pub No. WO 2016/100932 A1, published 23 June 2016, filed 18 December 2015) and Wennhold ("CD40-activated B cells induce anti-tumor immunity in vivo." Oncotarget 8.17 (2016): 27740).
This is a provisional nonstatutory double patenting rejection.
For the purposes of examination, the claimed limitation of “at least about the human equivalent of a dose of 1 x 107 cells in a mouse” is interpreted as being limited to 1 x 107 cells.
Regarding claim 52, copending claim 1 recites a method of administering genetically modified B cells to a subject for in vivo production of a therapeutic agent comprising: administering one or more doses of genetically modified B cells to a subject's central nervous system. Copending claim 15 claims that the subject is a human. Copending claim 11 recites that the genetically modified B cells can express IDUA. Copending claim 12 claims the determination and administration of multiple sub-optimal concentrations of the modified B cells, wherein the administration of multiple sub-optimal doses results in a greater than linear increase over lower dosages (i.e., copending claim 12 is interpreted as the synergistic production of the genetically modified B cells). Copending claims 57 and 59 claim that the subject has MPS I.
The copending claims do not claim that that two or more sequential doses of the B cells are separated by at least about one week and comprise a dosage of 1 x 107 cells (Claim 52).
Scholz is drawn to an invention concerned with differentiated B cell compositions for long term in vivo expression of a transgene and methods for producing the B cell compositions and use in prophylactic and therapeutic applications (Abstract; pg. 2). Scholz teaches that B cells may be contacted with a vector comprising a nucleic acid of interest (i.e., a polynucleotide) under conditions sufficient to transfect at least a portion of the B cells (pg. 21). Scholz teaches that the nucleic acid of interest may encode iduronidase (IDUA) for treatment or prevention of mucopolysaccharidosis type I (MPS I) (pg. 39). Scholz teaches that B cells expressing IDUA were able to successfully be administered to tissue culture media and express the IDUA within the tissue (pg. 5). Scholz teaches that B cell compositions may be administers multiple times at appropriate dosages, wherein the dosage comprises 1 x 107 cells (pg. 49). Scholz teaches that the optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly (pg. 49).
Wennhold is drawn towards a study concerned with how CD40-activated B cells can promote anti-tumor activity in vivo (Abstract). Wennhold teaches that multiple injections of CD40-B cells, at three intervals of 7 days each, could be utilized in a preventive vaccination approach for tumor targeting (pg. 27747; see Figure 5C and 5D). Wennhold teaches that, compared to a negative control, mice that had the B cells injected at the 7 day intervals demonstrated higher anti-tumor activity when the subject was challenged with melanomas (pg. 27747; see Figure 5C and 5D).
Thus, Wennhold teaches that the sequential administration of multiple doses of therapeutic B cells to a subject at the claimed 7 day intervals was a known method of treating a disease of interest through the use of the B cells.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the dose regimen of the copending claims such that at least two doses were administered and separated by at least 7 days because it would have merely amounted to a combination of prior art elements according to known methods to yield predicable results. Because Wennhold teaches the therapeutic administration of B cells to a subject, one would have expected that adopting the dosing regimen of Wennhold (i.e., multiple dosages separated by at least 7 days) in the method of the copending claims would have similarly resulted in synergistic production of IDUA in order to treat MPS I.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the copending amount of B cells administered for at least 1 x 107 cells because it would have merely amounted to simple substitution of one known element for another to obtain predictable results. Because both Scholz and the copending claims teach the administration of B cells that produce IDUA for the same purpose of treating MPS I, then one would have had a reasonable expectation of success in using the dosage amount of Scholz within the copending claims in order to achieve the same therapeutic benefit.
Claim 54 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-12, 15, 57, and 59 of copending Application No. 18/034,865 (reference application) in view of Scholz (PG Pub No. WO 2016/100932 A1, published 23 June 2016, filed 18 December 2015) and Wennhold ("CD40-activated B cells induce anti-tumor immunity in vivo." Oncotarget 8.17 (2016): 27740) as applied to claim 52 above, further in view of copending claim 23 and Ohlfest (Addgene (2009)) as evidenced by Monroe (Addgene blog (2014)).
Regarding claim 54, the copending claims in view of Scholz and Wennhold renders obvious claim 52 as described above.
Copending claim 23 claims that the therapeutic agent may be encoded on a viral vector to express the agent in the B cells.
Scholz further teaches that vectors may be utilized to deliver a transgene of interest to a B cell (pg. 21, lines 20-33). Scholz teaches that the vector may further comprise an EEK promoter and a DHFR selection marker (pg. 21, lines 16-32).
The copending claims in view of Scholz and Wennhold do not teach that the vector was a pKT2 vector (Claim 54).
Monroe is drawn to a review about how plasmids are designed and teaches that plasmid backbones can be modified by the insertion of a promoter, a selectable marker, and a gene of interest (pg. 2).
Ohlfest is drawn to a study concerned with the use of a pKT2 vector backbone (i.e., Ohlfest teaches that the pKT2 vector backbone was a known vector backbone) (pg. 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the vector of the copending claims in view of Scholz and Wennhold for the pKT2 vector backbone of Ohlfest and insert the EEK promoter, the IDUA gene of interest, and the DHFR selection marker disclosed in Scholz as described by Monroe. Because the copending claims, Monroe, and Ohlfest similarly teach the use of vector backbones that can be modified via the inclusion of multiple elements known to be useful to accomplish the same purpose of the copending claims (i.e., the expression of a recombinant nucleic acid), then a person of ordinary skill in the art would have had a reasonable expectation of success in substituting the claimed vector backbone, promoter, and selectable marker, alongside a gene encoding IDUA, and being able to express IDUA from the genetically modified B cells.
Response to Arguments
With regard to the arguments pertaining to the newly recited limitations, the newly recited 35 USC 103 rejections of record are discussed above as applied to claims 52 and 54.
With regard to the maintained double patenting rejection of record over US Application No. 18/034,865, Applicant’s arguments are not found persuasive.
Applicant alleges that because the present application has a patent term filing date of 27 April 2018 while the ‘865 application was filed 29 October 2021, the claims of the ‘865 application cannot serve as reference claims against the present application.
This argument is not found persuasive because MPEP 804 I.B.1.(b)(i) teaches that “if a provisional nonstatutory double patenting rejection is the only rejection remaining [emphasis added] in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent.” Therefore, since the currently pending nonstatutory double patenting rejection over US Application No. 18/034,865 is not currently the only remaining rejection of record, the nonstatutory double patenting rejection over US Application No. 18/034,865 is maintained. Once the currently pending nonstatutory double patenting rejection over US Application No. 18/034,865 is the only rejection remaining in the instant application, the rejection will be withdrawn.
Conclusion
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 KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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