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 .
Election/Restrictions
Applicant’s election without traverse of Group III in the reply filed on 9/15/2025 is acknowledged.
Accordingly, claims 1-3, 5, 7, 9, 1, 34, 36-40, 46 and 49 are withdrawn from consideration for being directed to non-elected subject matter. Claims 15, 16, 19, 20, 22, 24, 25, 28, 31 and 33 are currently under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/9/2024 has been considered by the examiner.
Claim Objections
Claims 15, 16, 19, 20, 22, 24, 25, 28, 31 are objected to because of the following informalities: it is suggested to amend claim 15 from “a sample selected from the group consisting of a bodily fluid sample from HIV-I-infected human or bodily sample from a HIV-1-infected population” to “a sample selected from the group consisting of a bodily fluid sample from HIV-I-infected human and bodily sample from a HIV-1-infected population” because when individual members of a group is recited in alternative, no selection is needed then. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 15, 16, 19, 22, 24, 28, 31 and 33 is/are rejected under 35 U.S.C. 102(a2) as being anticipated by Khalili (WO2015/031775, IDS).
Claim 15 is drawn to a method of treating HIV-1 infection comprising: 1) sequencing HIV-1 LTR regions that are integrated in the human genomic DNA from a bodily sample of infected human or a population of infected human; 2) identifying a set for guide RNA sequences that are at least partially identical to a fragment of the HIV-1 LTR; and 3) excising the HIV-1 chromosomally integrated genome from the human genomic DNA of the human using the set for gRNAs and the CRISPR system. Claim 33 is drawn such a method without the first sequencing step.
Khalili teaches a method comprises administering a composition comprising CRISPR-associated endonuclease and a guide RNA, the guide RNA is complementary to a target sequence in a human immunodeficiency virus such as HIV-1 or HIV-2 (abstract, and page 10, last paragraph, page 17, last paragraph). Khalili teaches the genetic variability of HIV is reflected in multiple groups and subtypes, and a collection of HIV sequences is compiled in the Los Alamos HIV databases and compendiums (page 17, last paragraph). Khalili teaches the guide RNA can be a sequence complimentary to HIV-1 LTR (page 18, 2nd paragraph). Khalili teaches in some embodiments, the method first determines the nucleic acid sequence of the particular HIV harbored by the patients and then designing the gRNA to be complementary to those particular sequences, i.e. LTR, U3, R or U5 region, and design one or more gRNAs to be precisely complementary to the patient’s sequences (page 36, 1st paragraph, bottom 5 lines). Khalili teaches one may develop personalized treatment modalities based on the data from deep sequencing of patient derived viral genome prior to engineering therapeutic Cas9/gRNA molecules (page 58, 2nd paragraph, last 3 lines). Since Khalili teaches every step of claim 15 and 33, the disclosure from Khalili anticipates the claimed invention of claim 15 and 33.
Regarding claim 16, since the specification does not provide any definition for next-generating sequencing, deep sequencing of patient derived viral genome taught by Khalili (page 58, 2nd paragraph, last 3 lines) meets this limitation.
Regarding claim 19, it is inherent that HIV-1 is highly mutagenic and evolving virus, and infection may comprise multiple strains of viral DNAs (page 58, 2nd col., line 6).
Regarding claim 22, Khalili teaches the gRNAs are complementary to LTR 5’ and 3’ ends (page 18, 2nd and 3rd paragraph).
Regarding claim 24, Khalili teaches the patients are also treated with other antiretroviral therapy such as HAART (page 11, 3rd paragraph).
Regarding claim 28, Khalili teaches the composition that comprises gRNA and CRISPR system can be delivered by liposome, hydrogel, microparticle, nanoparticle or a block copolymer micelle (page 33, 20-22).
Claim Rejections - 35 USC § 103
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.
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.
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.
Claim(s) 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khalili.
Regarding claim 25, although Khalili does not specifically teach at least two sequencing at different time points to be performed, it would have been obvious to an ordinary skilled in the art to recognize that evolving HIV-1 vQS would have different mutation(s) in viral sequence under selective pressure such as drug treatment. An ordinary skilled in the art would thus be motivated to sequence the bodily sample at two or more time points to determine the whether there is sequence variation of HIV-1 LTR and/or number of vQS. The ordinary skilled in the art would choose to administering the excising step when vQS is minimized to minimize the number of gRNAs required for treatment to reduce off target effects. Therefore, the claimed invention would have been obvious to an ordinary skilled in the art at the time the application was filed.
Claim(s) 20 and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khalili, in view of Kantor (Journal of Clinical Virology, 2004, Vol.29, pages 152-159).
The teaching from Khalili has been discussed above. Khalili further teaches the gRNA not only can be a sequence found within an HIV-1 reference or consensus sequence, but also can be selected to target any variant or mutant HIV sequence. Khalili teaches that gRNA can include a variant sequence or quasi-species sequence, or a sequence corresponding to a sequence in the genome of the virus harbored by the subject undergoing treatment (page 19, 3rd paragraph).
However, Khalili does not teach if the variant or mutation is vSNP (claim 20) when compared to a reference strain such as subtype B (claim 31).
Kantor teaches treatment of HIV-1 with antiviral therapy may select mutations in the pol gene associated with drug resistance, and subtype B of HIV-1 is well studied for drug resistance related to antiviral therapy in US and Canada (page 154, 1st col., 2nd paragraph, 2nd col., last paragraph). Kantor teaches a standardized RT and protease numbering system for HIV-1 drug resistance mutations has been developed, wherein all sequences are compared with a consensus B sequence (page 154, 1st col., 4th paragraph). Kantor teaches mutations at polymorphic and conserved sites that are associated with drug resistance in subtype B HIV-1 are found at high rates in untreated persons infected with non-subtype B HIV-1 (page 154, 2nd col., 4th paragraph).
It would have been obvious to an ordinary skilled in the art who performs the method taught by Khalili to first sequencing individual patient sample for the presence of vSNP following teaching from Khalili and Kantor, to identify whether the patient would be resistant to certain therapy as taught by Kantor. The ordinary skilled in the art would necessarily need to have a reference and/or consensus sequence to be compared to when determining the existence of vSNP. The ordinary skilled in the art would be motivated to use subtype B as a reference because it is well studied and drug resistant information are already in public knowledge at the time the application was filed. Therefore, the claimed invention of claim 20 and 31 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Note: The following 112 (a) rejection is based on the claimed method that is treating HIV-infection in human that is recited in preamble, whereas the above art rejection is based on the recited method steps which ends with excising HIV-1 chromosomally integrated genome in human cell.
Claim Rejections - 35 USC § 112
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.
Claim15, 16, 19, 20, 22, 24, 25, 28, 31 and 33 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 method of inactivating an integrated HIV-1 in a human cell comprising sequencing HIV-1 LTR that are integrated in the human genomic DNA from a sample; identifying a set of gRNA sequence that are partially identical to a fragment of the HIV-1 LTR region; and excising the HIV-1 chromosomally integrated genome from the human genomic DNA of the human cell using the set of gRNAs and CRISPR system, does not reasonably provide enablement for a method of treating HIV-1 infection in a human subject using gRNA and CRISPR associated system. 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/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." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
Claim 15 is drawn to a method of treating HIV-1 infection comprising: 1) sequencing HIV-1 LTR regions that are integrated in the human genomic DNA from a bodily sample of infected human or a population of infected human; 2) identifying a set for guide RNA sequences that are at least partially identical to a fragment of the HIV-1 LTR; and 3) excising the HIV-1 chromosomally integrated genome from the human genomic DNA of the human using the set for gRNAs and the CRISPR system. Claim 33 is drawn such a method without the first sequencing step.
The breadth of the claim
Claim 15 and 33 encompasses treating human infected with HIV-1 by sequencing any region in LTR of HIV-1 and design gRNA based on the sequence information to excise the HIV-1 from human subject.
The teaching from specification and the presence of working examples
The specification teaches sequencing 6 patients and 8 samples to gain information for the conservation of the HIV-1 LTR and number of gRNAs potentially needed per patient to target all known quasi-species. The specification teaches that a complete gRNA regime could only be designed for 4/8 patients, and a regime with less than 10 gRNAs can be devised for one subset of patient, whereas no regime can completely excise their infection (page 35, 2nd paragraph). The specification teaches designing gRNAs from the Drexel Medicine CARES cohort patients and measuring their effectiveness on CARES cohort patient samples and other samples using computational bioinformatic tools (Example 3 and 4). However, the specification does not teach or provide an example that the identified gRNAs lead to any therapeutic treatment in a human patient or a whole animal model for HIV-1 infection.
The state of prior art and the level of predictability in the art
The closest prior art to the claimed invention is Dampier et al (IDS), which describes the same experimentation as disclosed in example 1-4 of the present application. However, Dampier also discussed challenges for designing gRNAs that targeting all of the integrated viral LTRs will be complex (page 5, line 1-2). Dampier also states “along with the challenge of designing the gRNAs necessary for the excision of all integrated virus, the other major challenge will be delivery of the gRNAs…given these challenges, immediate studies are needed to explore these issues…” Dampier also suggests some questions needs to be answered including what are the viral dynamics in the cells, how long must a patient be on ART to drive virus selection in the reservoir to a level where the number of quasi-species present is low enough to limit the gRNAs needed to eradicate the retention of viral proviral DNA in these tissues? Dampier concludes that while the prospects of the technology remain very exciting, “it is reasonable that this type of therapy is still at least 5-10 years away from being able to be considered as an effective therapy in human.” (page 6, lines 1-7). As such, whether the gRNA identified in the present application may in fact lead to HIV-1 treatment in a human patient is still unpredictable at the time the application was filed.
The amount of experimentation required
Due to the art recognized challenges for the method of treating HIV-1 infection using CRISPR and gRNA targeting HIV-1 LTR, a skilled artisan would have to rely solely on the teaching from the specification to practice the method to its full scope. However, the specification does not provide any evidence that identified gRNA can in fact treat HIV-1 infection in either an animal model or human patient. Nor does the specification answers the questions as discussed above in Dampier publication. As such, a skilled artisan would have to engage in undue experimentation to practice the invention to its full scope for claims 15, 16, 19, 20, 22, 24, 25, 28, 31 and 33. Therefore, the claimed invention is only enabled to the scope discussed above.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/Primary Examiner, Art Unit 1637