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 .
Claim Status
The amendment of 11/10/2025 has been entered. Claims 1-9 and 11-20 are pending in this US patent application. Claims 3-9 and 11-15 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/08/2022.
Claims 1-2 and 16-20 are currently under examination and were examined on their merits.
Claim Interpretation
Amended claim 1 recites a method of administering a neuron-editing biologic in combination, applying a brain region activator comprising transcranial pulsed ultrasound to the subject, and focusing transcranial pulsed ultrasound on the targeted brain regions of the subject. Amended claim 1 further recites “activating neurons of the targeted brain regions of the subject, causing them to become activated neurons; directing the neuron-editing biologic to the targeted brain regions in a brain of the subject via hemodynamic vectoring; and increasing uptake of the neuron-editing biologic in a bloodstream of the subject by the activated neurons of the targeted brain regions”. The phrases “activating neurons of the targeted brain regions of the subject, causing them to become activated neurons; directing the neuron-editing biologic to the targeted brain regions in a brain of the subject via hemodynamic vectoring; and increasing uptake of the neuron-editing biologic in a bloodstream of the subject by the activated neurons of the targeted brain regions” represent the intended results of practicing the positively recited method steps of administering a neuron-editing biologic in combination with a brain region activator, applying a brain region activator comprising transcranial pulsed ultrasound to the subject, and focusing transcranial pulsed ultrasound on the targeted brain regions of the subject. See instant specification as filed, pages 6-8 and 10, which indicate that the steps of claim 1 performed by the individual performing the method are administering, applying, and focusing, and the steps of activating, directing, and increasing uptake intrinsically occur in the subject following the steps of administering, applying, and focusing. A clause in a method claim does not receive weight when it simply expresses the intended result of a process step positively recited. See MPEP § 2111.04 (I). As such, any prior art that reads on the positively recited method steps of claim 1 (i.e., the selecting and focusing steps) will be interpreted to read on the entirety of claim 1, regardless of whether the prior art recites the specific results of the steps recited in claim 1.
Additionally, given the lack of any further limitation on the targeting or the regions, the Examiner notes that “targeted brain regions” can be any brain regions.
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 1-2 and 16-20 remain rejected under 35 U.S.C. 103 as being unpatentable over international patent application WO 2018/035388 filed by Zhang et al., published 02/22/2018, in view of US patent application 2013/0079682 filed by Mischelevich, published 03/28/2013.
Please note that this rejection has been slightly augmented to incorporate discussion of the newly-added limitations to claim 1. However, because the basis of the rejection is unchanged, the rejection has been maintained.
Zhang teaches an engineered CRISPR-Cas effector protein that complexes with a nucleic acid comprising a guide sequence to form a CRISPR complex, and wherein in the CRISPR complex the nucleic acid molecule targets one or more polynucleotide loci and the protein comprises at least one modification compared to the unmodified protein that enhances binding of the CRISPR complex to the binding site and/or alters editing preferences as compared to wild type (see entire document, including page 3, paragraph 0010). The invention provides a method of altering the expression of a genomic locus of interest in a mammalian cell (page 58, paragraph 0206), and the CRISPR-Cas system can be delivered to the brain or neurons (page 402, paragraph 1292; cf. claims 1 [“A method for modifying neurons in targeted brain regions of a subject comprising administering a neuron-editing biologic to the subject”] and 19; the Examiner notes that, because the disclosure does not define any method by which brain regions are considered “targeted”, any brain region can be interpreted as a “targeted” brain region). In some embodiments, the guide sequence is a modified guide RNA or a dead gRNA (pages 300-301, paragraph 0933; cf. claim 2; the Examiner notes that CRISPR is a catalytically-active gene-editing endonuclease and that a modified or dead gRNA could be interpreted as a “synthetic guide RNA”). The release of the CRISPR-Cas complex can be targeted to brain tissue, brain ventricles, or degenerative sites in the brain (pages 224-225, paragraph 0695; cf. claim 1 [“…the neuron-editing biologic targets neuron cells over non-neuron cells”]; the Examiner notes that targeting the complex to the brain tissue will intrinsically result in the targeting of neuron cells, which comprise a large proportion of brain tissue, over the non-neuron cells of the rest of the body) and associated with focused ultrasound and low frequency ultrasound methods (page 225, paragraph 0697; page 235, paragraph 0736; cf. claim 1 [“…applying a brain region activator”]).
However, Zhang does not teach that the focused/low-frequency ultrasound administered to deliver the CRISPR-Cas complex to certain areas of the brain is transcranial pulsed ultrasound as recited in instant claim 1.
Mischelevich teaches noninvasive ultrasound neuromodulation techniques to selectively alter the permeability of the blood-brain barrier (see entire document, including page 2, paragraph 0012). Ultrasound results in the generation of action potential in neurons (page 1, paragraph 0006). For neural targets, the application of the invention may result in effective neuromodulation of the neural target in addition to altering the permeability of the blood-brain barrier to allow more effective penetration of a drug to impact that neural target (page 2, paragraph 0018; cf. claims 1 [“…applying a brain region activator comprising transcranial pulsed ultrasound to the subject; focusing transcranial pulsed ultrasound on the targeted brain regions of the subject; activating neurons of the targeted brain regions of the subject, causing them to become activated neurons; directing the neuron-editing biologic to the targeted brain regions in a brain of the subject via hemodynamic vectoring; and increasing uptake of the neuron-editing biologic in a bloodstream of the subject by the activated neurons of the targeted brain regions”] and 16-20 [“…applying the brain region activator comprises focusing the…ultrasound on the targeted brain regions”]; see above under Claim Interpretation for the Examiner’s interpretation of the intended results recited in instant claim 1). The ultrasound is pulsed (page 3, paragraph 0020) and is focused on particular regions of the head at lower frequencies than those used for imaging applications (page 3, paragraph 0021; cf. claims 1 and 16-20 [“…applying a brain region activator comprising transcranial pulsed ultrasound to the subject; focusing transcranial pulsed ultrasound on the targeted brain regions of the subject; activating neurons of the targeted brain regions of the subject, causing them to become activated neurons; directing the neuron-editing biologic to the targeted brain regions in a brain of the subject via hemodynamic vectoring; and increasing uptake of the neuron-editing biologic in a bloodstream of the subject by the activated neurons of the targeted brain regions” (claim 1); “…wherein the brain region activator is transcranial pulsed ultrasound” (claims 16-20); “…focusing the transcranial pulsed ultrasound on the targeted brain region focuses and concentrates the neuronal activity in the targeted brain regions” (claim 16); “targeting regions of the brain with the brain region activator” (claims 18-19); “…focusing the transcranial ultrasound on the targeted brain regions targets the regions of the brain” (claim 19); “…focusing and concentrating neuronal activity in the targeted brain regions, wherein administering the brain region activator comprises focusing the transcranial pulsed ultrasound on the targeted brain regions, and focusing the transcranial pulsed ultrasound on the targeted brain regions focuses and concentrates the neuronal activity in the targeted brain regions” (claim 20)]; the Examiner notes that the claims are worded in such a manner as to indicate that “activating neurons of the targeted brain regions increases uptake of the neuron-editing biologic in the bloodstream of the subject by the activated neurons of the targeted brain regions via hemodynamics” and “focusing and concentrating the neuronal activity in the targeted brain regions” are the intended results of the positive method step “focusing the transcranial pulsed ultrasound on the targeted brain regions,” and intended results do not receive patentable weight; see MPEP § 2111.04 (I)).
The ultrasound is transmitted through the skull and to brain targets (page 3, paragraph 0024; cf. claims 1 and 16-20 [“…transcranial”]). The ultrasound treatment to increase the permeability of the blood-brain barrier may up-regulate the neural targets and may excite the neurons (page 1, paragraph 0006; page 2, paragraphs 0014 and 0019; see also claims 1 and 20-21; cf. instant claims 1, 17, and 20 [“…applying the brain region activator comprises focusing the transcranial pulsed ultrasound on the targeted brain regions such that the transcranial pulsed ultrasound converts neurons of the targeted brain regions into active neurons that are firing…the brain region activator directs the neuron-editing biologic by converting neurons into active neurons that are firing…targeting regions of the brain with the brain region activator such that the brain region activator selectively converts neurons of the targeted brain regions into active neurons that are firing” (claims 17 and 20)]; the Examiner notes that neurons having action potentials, as the reference teaches is a result of ultrasound treatment, are “active neurons that are firing” and that “up regulating” and “excitation” would result in the generation of action potentials; the Examiner further notes that the wording of the instant claims indicates that “[directing] the neuron-editing biologic” is a result of the positive method step “converting neurons into active neurons that are firing”).
While Zhang does not teach that the focused/low-frequency ultrasound administered along with the CRISPR-Cas complex delivered to certain areas of the brain is transcranial pulsed ultrasound, it would have been obvious to one of ordinary skill in the art to deliver the CRISPR-Cas complex of Zhang with transcranial pulsed ultrasound because Zhang teaches that the targeted administration of the CRISPR-Cas complex, which can occur to particular brain regions, can be associated with focused ultrasound techniques and because Mischelevich teaches that transcranial focused ultrasound using a pulsed wave can be used to administer drugs to the brain while also performing neuromodulation. One of ordinary skill in the art would have a reasonable expectation that using the transcranial pulsed ultrasound of Mischelevich as the focused ultrasound of Zhang would successfully result in the targeted delivery of the CRISPR-Cas complex of Zhang to neurons for editing.
Therefore, claims 1-2 and 16-20 are rendered obvious by Zhang in view of Mischelevich and are rejected under 35 U.S.C. 103.
The Supreme Court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation…103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions……the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) (emphasis added).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant has traversed the above rejection of the claims under 35 U.S.C. 103 as being unpatentable over Zhang in view of Mischelevich. Applicant states that the cited references teach only activating drug delivery systems or opening the blood-brain barrier and do not teach that focusing transcranial pulsed ultrasound on selected regions of the brain will draw neuron-editing biologics into neurons via hemodynamics regardless of whether such transcranial pulsed ultrasound also opens the blood-brain barrier or that rationales may be used to target specific regions of the brain to address specific concerns. Applicant states that Mischelevich’s teachings regarding the benefits of transcranial pulsed ultrasound amount to teaching away from performing the recited selection step (remarks, pages 6-10). This argument has been fully considered but has not been found persuasive.
The Examiner notes that Applicant’s claims are sufficiently broad to encompass directing the biologic by any means, including by opening the blood-brain barrier, and to encompass directing the biologic to any brain region, including the entire brain. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The Examiner further notes that it does not matter why the prior art is performing the recited steps, whether for “brain region activation” or for “opening the blood-brain barrier” or for “activating a drug delivery device” or “controlling hemodynamics.” Applicant is citing intended results. What matters for obviousness is the actual steps that are performed by the person undertaking the claimed method. The effects that these steps have in the body of the patient receiving the recited treatment are not steps that Applicant is performing. They are inherent results of the steps performed by the experimenter. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Therefore, the Examiner has maintained the rejections presented above.
Conclusion
No claims are allowed.
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 Erin M. Bowers, whose telephone number is (571)272-2897. The examiner can normally be reached Monday-Friday, 7:30-5:00.
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/Erin M. Bowers/Primary Examiner, Art Unit 1653 03/04/2026