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 .
Priority
The instant application, filed on 03 April, 2024 is a 371 of PCT/US2022/045632 filed 04 October, 2022 and claims domestic benefit to US provisional application no. 63/252,890, filed on 06 October, 2021.
Status of Application, Amendments, and/or Claims
The response filed on 03 April, 2024 has been entered in full. No amendments or withdrawals have been made. Therefore, claims 1-26 are pending and are the subject of this Office Action.
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.
Claims 1 20, 21, and 23 rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claims 1 and 23 recites “and allowing a UCA antibody designed to target those cell expressing the UCA.” This sentence is unclear as the sentence does not discuss what the “antibody designed to target those cells expressing the UCA” is being allowed to do, therefore rendering the claims indefinite. For the purpose of further examining the claims will be interpreted as allowing an anti-UCA antibody to target those cells expressing the UCA.
Claims 20 and 21 recite the limitation "the method of claim 18, wherein the shots". There is insufficient antecedent basis for this limitation in the claim. Claims 20 and 21, or 18 do not recite shots, however claim 19 recites “the CRISPR detector and mRNA payload are provided in separate shots.” For the purpose of further examination, the claims will be interpreted to depend on claim 19 instead of claim 18.
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.
Claims 19-21 are rejected under 35 U.S.C. 112(a), as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification does not provide enablement for the scope of the claim in regards to administering the CRISPR detector and mRNA as separate shots (Claim 19), simultaneously (Claim 20) or sequentially (Claim 21).
The enablement requirement is such that the specification of the described invention is in such terms that one skilled in the art can make and use the invention to ensure that the invention is communicated to the interested public in a meaningful way (See MPEP 2164).
The standard for determining whether the specification meets the enablement requirement is determined in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not me undue experimentation. The key word is ‘undue,’ not ‘experimentation’.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered a sufficient amount for a prima facie case are described below.
The Nature of the Invention
The instant claims encompass a method of treating cancer-associates mutation comprising; identifying a mutation, detecting the mutation using a CRISPR detector with an mRNA payload, and releasing the mRNA payload upon detection of the mutation to express a universal cancer antigen and further allowing an antibody to bind to the universal cancer antigen as recited in claim 1. Further claims 19-21 encompass delivering the CRISPR detector and mRNA payload separately.
The Breadth of the Claims
The claims are broad in that they encompass any treatment of cancer wherein a CRISPR detector and mRNA payload are administered in two shots in any timing sequence.
The amount of direction provided by the inventor/ the existence of working examples
The example in the instant disclosure discusses a vaccine platform in which the CRISPR detector and the mRNA payload are delivered in separate Injections, wherein the CRISPR detector has a “key” (a chemical compound released upon detection) and the mRNA has a “lock” (pg.27, lines 3-9).
The disclosure does not discuss how the CRISPR detector and the chemical compound would be integrated with one and other to facilitate the release upon detection of the target sequence, and further does not describe how the mRNA payload would be trafficked to the site of the target sequence or how the “lock” is configured for the mRNA releases.
The state of the prior art/ the level of predictability in the art
There are no recognized methods that can be used to predictably determine the “key” and “lock” mechanism which would allow for mRNA trafficking and release upon CRISPR detection. Rather, the state of the art discusses releasable transporter of mRNA independent of CRISPR, and CRISPR collateral activities and ability to cleave nearby ssDNA or ssRNA for fluorescent signaling. The prior art is silent as to target marking and trafficking using a CRISPR detector.
For example, McKinlay et al. (2017) Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals Proc. Natl. Acad. Sci. U.S.A. 114 (4) E448-E456 (hereafter McKinlay), teaches a mRNA delivery system comprising charge altering releasable transporters which function initially as polycations that noncovalently complex, protect, and deliver polyanionic mRNA and then subsequently lose their cationic charge through a controlled self-immolative degradation to a neutral small molecule (pg.E448, col 2, line 21 – pg.E449, col 1, line 7/ Fig 1). McKinlay further teaches these are nontargeted complexes (pg.E453, col 2, line 22).
Thus, McKinlay discusses a releasable mRNA payload but is silent on trafficking this payload to specific cells through signaling or marking to target cells.
English et al. (2019) Programmable CRISPR-responsive smart materials Sciences 365, 780-785 (hereafter English), teaches a CRISPR responsive hydrogel material in which sequence specific activation allows for the release of small molecules, enzymes, nanoparticles, and live cells, and can be used in sensing and detection (pg.1, col 2, lines 7-23). However, English only teaches a system in which the Cas endonuclease and cargo are conjugated and the payload is released by hydrolysis of the ssDNA anchor by the introduction of scrambles control (pg. 1, col 3, lines 53-61/ Figure 1).
Thus, English highlights a CRISPR mediated releasable cargo but demonstrates the payload must be attached to the CRISPR in order to be released upon detection of the target sequence.
Huang et al. (2018) Application of CRISPR-Cas Enzymes in Cancer Therapeutic and Detection Trends Cancer. 4(7) (Author’s Manuscript) (hereafter Huang), teaches both Cas12a and Cas13a are options for detection of mutations, and further have enzymatic activities which allow them to fluorescently mark the target cells for detection, however these florescent markers are attached to the CRISPR during delivery (pg.7, lines 8-26 / pg.7, lines 35 – pg.8, line 13).
Together McKinley, English and Huang demonstrate that it is known in the field how to use CRIPSR systems to specifically release payloads upon target detection, however, these payloads must be attached to the CRISPR systems to facilitate their release. The arts together are silent on how these systems could be used to mark a target cell to traffic a payload to a specific target cell.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed above, there is no disclosed or art recognized method through which an ordinary person skilled in the art would be able to determine how the “key and lock” mechanism would work for separate delivery of the CRISPR detector and mRNA payload. As such, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to identify a method that could be used to determine how to configure the CRISPR to release a chemical compound upon detection and further which chemical compounds are capable of performing said function.
In view of the wands factors discussed above, instant claims 19-21 are determined to not meet the enablement requirement of 35 U.S.C. 112(a).
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.
Claims 1, 2, 3, 5, 16, 17, and 22-26 are rejected under 35 U.S.C. 103 as being unpatentable over Shuber (US 2021/0121581, priority date: 10/20/2019) in view of Kowalski et al (2019) Delivering the Messenger: Advances in Technologies for Therapeutic mRNA delivery Molecular Therapy 27(4) 710-728 (hereafter Kowalski).
In regards to claims 1, 2, 17, 22 and 23 Shuber teaches a genome editing tool which comprises a Cas endonuclease (CRISPR detector) and a neoantigen (universal non-naturally occurring cancer antigen) coding sequence selectively target a tumor genome by acting on sequences found specifically in the tumor genome (nucleic acid mutation). The Cas endonuclease cleaves the tumor specific sequence and allows for insertion and integration of the exogenous neoantigen coding sequence (pg.1, col 1, paragraph 004, lines 1- 15). In regards to claim 3 Shuber teaches the Cas endonuclease is complexed with guide RNAs to complimentary to the target DNA (pg.2, col 1, paragraph 0013).
In regards to claim 5 Shuber teaches the insertion and integration of the coding sequence allows for the expression of the neoantigen on the surface of the tumor cell to mark the tumor cell for dearth by the immune cell or an antibody-drug conjugate (pg.1, col 1, paragraph 004, lines 15- 24).
In regards to claim 16 Shuber teaches the composition can be an injectable preparation (shot) (pg.10 , col 1, lines 16-18) which contains one or more particles comprising the Cas endonuclease and the expression cassette (a single shot) (pg.3, col 1, lines 31-37).
Shuber fails to teach the mRNA payload of claim 1, 17, 22, and 23, the non-replicating mRNA of claim 24 and, the virally derived mRNA of claim 25 and the self-amplifying RNA of claim 26.
Kowalski, however, in regards to claims 1, 2, 17, 22, and 23 teaches that mRNA is a method of inducing the expression of therapeutic proteins with potential to treat a wide range of diseases (pg.714, col 2, lines 13-14). Kowalski also teaches these mRNAs can be engineered to display low immunogenicity, prolonged stability, and potent translation (pg.714, col 2, lines 21-22). Further Kowalski teaches mRNA based therapies have features such as, a low risk of insertional mutagenesis, transient production of encoded protein, and cytoplasmic activity of mRNA lowering the cellular barriers for functional delivery (pg.714, col 2, lines 29-32).
In regards to claims 24-26 Kowalski teaches there are two subtypes of RNA vaccines, which includes non-amplifying (non-replicating) and self-amplifying (pg.718, col 2, lines 3-5). Kowalski also teaches non-amplifying mRNA is beneficial because they are relatively small, lack additional proteins which could possible elicit undesired immunogenic interactions, are easy to scale up and manufacturing, and facile sequence engineering (pg.719, col 1, lines 5-11). Alternatively, self-amplifying mRNA is virally derived and is beneficial because they extend the duration and magnitude of expression compared to non-amplifying (pg.719, col 2, lines 15-16/pg.719, col 2, lines 20-23).
Thus, Shuber discloses a genome editing tool which comprises a Cas endonuclease and a neoantigen coding sequence selectively target a tumor genome by acting on sequences found specifically in the tumor genome and further wherein an antibody against the neoantigen is administered to induce cell death, and Kowalski teaches mRNA is a method of inducing the expression of therapeutic proteins which have a low risk of insertional mutagenesis, transient production of encoded protein, and cytoplasmic activity of mRNA lowering the cellular barriers for functional delivery. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Shuber and Kowalski with a reasonable expectation of success to simply substitute the expression cassette of Shuber with mRNA to develop a gene editing tool with improved functional delivery, and lower risk of insertional mutagenesis for a more effective therapeutic.
Claims 6-15 and 18, are rejected under 35 U.S.C. 103 as being unpatentable over Shuber in view of Kowalski as applied to claims 1 and 17 above, and further in view Ishiguro et al. (2017) An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors Sci. Transl. Med. (9) eaal4291 (hereafter Ishiguro) and Blass and Ott (2021) Advances in the development of personalized neoantigen-based therapeutic cancer vaccines Nat Rev Clin Oncol 18, 215–229 (hereafter Blass and Ott) as evidenced by Schaaf et al. (2018) Defining the role of the tumor vasculature in antitumor immunity and immunotherapy Cell Death and Disease 9:115 (hereafter Schaaf).
Shuber in view of Kowalski fails to teach the various immune responses induced by the antibody of claims 8, 9, and 11-15, and further administering an adjuvant of claim 15, and the antibody provided in a vaccine of claim 18.
Ishiguro, however in regards to claims 14 and 18 teaches the administration of a bispecific antibody vaccine which expresses CD3 and anti-glypican 3 (GPC3) (Fig 1A), which allows it to bind to both T-cells and GPC3, a tumor specific antigen expresses almost exclusively in tumor cell (pg.2, col 2, lines 34-41), which redirects the T cells to activate them to kill cancer cells (pg.1, col 2, lines 11-13).
In regards to claim 6 Ishiguro teaches, the bispecific antibody increases the T-cell dependent cellular cytotoxicity (effector function) in a concentration dependent manner (pg.2, col 2, lines 47-48 / pg.3, col 1, lines 2-5/ Figure 4).
In regards to claim 7 Ishiguro teaches that the bispecific antibody downregulates the gene expression of VEGF in the Hepa1-6/hGPC3 tumor model and VEGFR1 and VEGFR2 in the LLC1/hGPC3 tumor model (Figure 5B). These are both indicative of reducing angiogenesis which is evidenced by Schaaf which teaches targeting the VEGF/VEGFR axis can blocking survival and growth of blood vasculature (angiogenesis) and induce vascular normalization which can improve elicit better therapeutic outcome (pg. 9, col 2, lines 1-4/ pg.10, col 1, lines 10-16). Therefore, Ishiguro teaches a bispecific antibody which can reduce angiogenesis as evidenced by Schaaf.
In regards to claim 8 Ishiguro teaches, this bispecific antibody platform resulted in further upregulation of immune related genes (activated an immune response) in both immunogenic and nonimmunogenic tumors (pg.4, col 2, lines 11-13/ Figure 5B).
In regards to claim 9 Ishiguro teaches, the bispecific antibody had marked tumor growth inhibition in vivo (reduced tumorigenesis) (pg.3, col 2, lines 28-29/ Figure 4C).
In regards to claims 11, 12, and 13 Ishiguro teaches administration of the antibody affects the expression of various cytokines including interleukins such as IL-10 and IL-6, as well as the interferon IFNg (Figure 5B).
In regards to claim 15, Ishiguro teaches further administering dexamethasone (an adjuvant) in combination with the bispecific antibody (Figure 7 C/D) to decrease cytokine production to prevent cytokine release syndrome (pg.7, col 1, lines 9-12) while maintaining anti-tumor T-cell activity (pg.10, col 1, lines 25-29).
Ishiguro fails to teach the antibody activating a memory cell immune response of claim 10, however, Blass and Ott teach the immunological cascade following vaccination induces the innate immune response which primes the T cells and antigen specific T cell responses then undergo expansion, followed by antigen clearance which culminates in the generation of a population of long lived memory T cells (pg.220, col 2, lines 4-12). Further Blass and Ott teach that the quality and magnitude of the CD8+ T cell responses can be influenced by various factors such which result in variable memory T cell populations and in the context of cancer effective T cell responses can be induced by regulatory T cell suppression or tolerogenic T cell priming by DCs (pg.220, col 2, lines 31-39).
Thus, Shuber in view of Kowalski discloses a genome editing platform for targeting cancer mutations which also contains mRNA payload to be delivered and induce the expression of a target antigen which is then targeted by an antibody, Ishiguro teaches a bispecific antibody which can be delivered to target a tumor specific target and induces and immune response, and reduce angiogenesis and tumorigenesis, and Blass and Ott teach that a memory cell immune response is part of the immunological cascade and that is can be tuned by various factors. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Shuber in view of Kowalski with the teachings of Ishiguro, and Blass and Ott to develop a gene editing platform which targets cancer mutations to induce a target antigen expression, and further to administer a bispecific antibody that engages both a tumor specific target antigen and a T cell, further wherein the immunological cascade elicits a memory T cell response, the with a reasonable expectation of success to tunable, highly-targeted, and long lasting treatment platform that supports an immune response which is successful at treating cancer.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Shuber in view of Kowalski as applied to claim 1 above, and further in view of Huang et al. (2018) Application of CRISPR-Cas Enzymes in Cancer Therapeutic and Detection Trends Cancer. 4(7) (Author’s Manuscript) (hereafter Huang).
Shuber in view of Kowalski fails to teach the identified nucleic acid being RNA, however, Huang teaches Cas13s is an RNA-guided RNA-targeting CRISPR endonuclease with an allosteric switch for RNase activity (pg.6, line 32 / pg.6, lines 39 – pg.7, line 1). Cas13a has been used for multiplexed RNA interference, target detection through reporter cleavage, and multiplexed target detection (pg.7, lines 4-7).
Thus, Shuber in view of Kowalski discloses a genome editing platform for targeting cancer mutations which also contains mRNA payload to be delivered and induce the expression of a target antigen which is then targeted by an antibody, and Huang teaches the CRISPR endonuclease Cas13a is RNA-guided and RNA-targeting and has an allosteric switch and can be used for target detection. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Shuber and Kowalski with the teaching of Huang to simply substitute the Cas endonuclease with the Cas13a endonuclease to enable the detection of target RNA mutations with a reasonable expectation of success to allow for the targeting, multiplexed targeting, or multiplexed RNA interference for a more adaptable platform to target the mRNA payload.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Thursday from 8am to 6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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