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 .
Acknowledgment of Papers Received: Amendment/Response dated 9/8/25.
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.
Claim(s) 1-19, 21 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over During (US 2019/0060400 hereafter During) in view of Shapiro (US 20140288421 hereafter Shapiro), Chu (Focused Ultrasound-Induced Blood Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed, Scientific Reports, 6:33264, 2016) and Roth (DREADDs for Neurosceintists, Neuron 89, 2016).
During discloses a method to control a target brain cell activity in an individual by applying a focused ultrasound to a target brain region [0039, 0116]. An effective amount, 25 µL of a of a microbubble contrast agent is systemically administered to the individual [0117]. The focused ultrasound and the systemically administered microbubble contrast agent are performed to induce transient blood-brain barrier opening at the target region [0118, 0126], meeting the combination limitations of claim 15. An effective amount if an AAV expression vector, in injected into the sclerotic hippocampus on day 21 [0120], meeting claims 13. Later, on day 42, subjects are evaluated for ultrasound effects [0120], meeting the limitations of claims 17. During discloses that the ultrasound makes the blood-brain barrier more permeable, meaning the vector along with the ultrasound application are configured to open the barrier [0018]. The gene encoding a chemogenetic protein (hM4D) is under the control of a promoter (CaMKII), which is a cell-type specific promoter for excitatory neuron [0038]. Thus the protein is configured to activate or inhibit the target brain cell activity following binding with the corresponding chemical actuator.
During is silent to the specific mechanical index of the ultrasound, however, During teaches an overlapping frequency and pressures (0093). During teaches the variability of frequency and amplitude but is silent regarding the mechanical index of the method. However, at the time of filing, one of ordinary skill in the art would have found optimizing the MI through no more than routine experimentation obvious. Chu is also concerned with focused ultrasound and its ability to create transient BBB openings, as described also in During. Chu teaches that the mechanical index relates to how "aggressive" the BBB openings are, noting that a MI of 0.41 (within the claimed range) creates mild openings at both 0.4 MHz and 1 MHz (both within the instant range of claims 6 and 7). Chu also teaches the duration of the pulses is a result-effective variable (p.1), including exemplary burst lengths of 10-50 ms (p.9), which overlaps the instant range and therefore establishes a prima facie case of obviousness (MPEP 2144.05). As such, one of ordinary skill in the art, provided with all of the general conditions of the method by During as well as the effects of altering MI on BBB openings provided by Chu would have arrived at the instant range with no more than routine experimentation of a known result-effective variable, rendering the claim obvious.
Further, it is also noted that this is the intention of, and a result taught by, During. During teaches the applying focused ultrasound, administering contrast agent, and administering chemogenetic protein vector is for the purpose of then expressing that protein in a subset of brain cells (target brain cells) to treat those cells (e.g., to treat seizure by inhibiting those target cells). The target brain cells would therefore comprise the chemogenetic protein. During also teaches administering different doses of the vector (paragraph 76), thereby teaching control of the percentage population of the target brain cell in the target brain region which is chemogenetically treated. See instant paragraph 135 noting that the amount of vector dose alters the amount of cells transfected, i.e., the "controlled percentage".
Finally, even considering that During is silent regarding the transfection efficacy rate of the method, During teaches varying the amount of vector administered depending on a number of factors (paragraph 84) and the amount of vector administered determines the percent of cells expressing the protein; see instant paragraph 135 noting that the amount of vector dose alters the amount of cells transfected, i.e., the "controlled percentage". Thus, varying the dose to achieve a desired expression percentage represents no more than routine optimization of a prior art method.
Additionally, Shapiro teaches that when using gene vectors to transfect a cell, it may be used such that all cells in the area of administration are transfected (paragraph 36), thereby teaching that up to 100% (at least 20%) of target brain cells in a target brain region may be made to express the chemogenetic protein of During, making such a choice obvious in a method designed to transfect cells for a therapeutic purpose.
Further During teaches a brain region size that overlaps with the instant range of less than 10mm. During teaches the target region varies in size according to the volume of tissue/fluid for vector delivery desired and provides the example of about 0.1 mm³ to about 5 cm³ [50 mm³; 0093]. Where the prior art range encompasses the claimed range, a prima facie case of obviousness exists (MPEP 2144.05). The target region is designated not out of necessity of the method but by the desires of the user, i.e., it is a result-effective variable. During teaches "about" is broadly used and also determined by the user [0099] and there is no allegation of criticality or evidence of any difference across the range. It is also of note that the target brain region must be less than 10mm, which is a description of the two dimensional length/diameter of a three dimensional volume. The planar measurements of a 0.1 mm³ volume would be understood to have a 2D "size" of 0.1mm, i.e., the length of one face.
During teaches administering 5-8E8 bubbles per mL, using 25 µL, to a mouse, but does not disclose the weight of the mouse and so the amount of bubble per kg cannot be determined. First, it is noted that 1E8 is an alternate means of expressing 1x10⁸ and would have been familiar notation to the ordinary artisan. During teaches 5.0-8.0x10⁸ bubble per mL, which equals 5-8 X 10⁵ bubble per µL. Using the volume of 25 µL, During administers 125-200x105 bubbles, which is mathematically equivalent to 1.25-2x10⁷ bubbles. As evidenced by Jax (form 892), mouse weights vary but an adult female mouse may reasonably weigh 20g, which translates into a dose of 6.25-10x10⁸ bubble/kg for a female mouse, which is within the range instantly claimed. Even with the stipulation that all 50 mice of During would have had different weights, this establishes that the ranges at least overlap the instant range.
Further, where the general conditions of the method are present and the only difference is in the amount of microbubble contrast agent being administered, optimizing this concentration is no more than the discovery of optimum or workable ranges by routine experimentation and insufficient to render an otherwise obvious method non-obvious. Further, Shapiro notes that the amount of contrast agent is variable (paragraph 15, 38, 41), thereby teaching that the microbubble contrast agent concentration is variable.
During teaches administering 4.66E13 copies (vectors)/mL to a mouse and that this amount is variable, but does not disclose the weight of the mice and so amount/kg cannot be determined. The reference teaches 4.66x10¹³ copies per mL (paragraph 112), which equals 4.66x10⁷ copies/nL. Using the volume of 500 nL, and the math above, this is roughly 1.17x10¹² copies/kg for a female mouse, which is below the range instantly claimed. However, the amount of viral particles administered were known to be a result-effective variable. In addition to the value which was reduced to practice, During teaches the variability of the vector including considerations to take into account when formulating doses (paragraphs 76,84) such as noted above and the rationale for varying the amount-to alter the amount of cells expressing the protein-was also known as noted above. The amount will vary not only due to optimizing the number of cells expressing the protein but will vary by subject; administration to the mouse in During will not be measured as particles per kilogram and During teaches varying subjects such as humans, canines, felines, etc (paragraph 106). Thus, optimizing the amount of viral particles per kilogram to administer represents no more than routine efforts in the art and it is not inventive to determine such values. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP $2144.05(II).
With these aspects in mind, the differences between the instant claims and the prior art would have been obvious to one of ordinary skill at the time of filing for the reasons articulated above. Regarding claim 2 and 3, the same rationale for arriving at "at least 20%" applies to "at least 40%". During teaches a n ultrasound at 0.69 MHz, meeting claims 5 [0093]. The reference teaches a vector of AAV9 meeting the limitations of claim 7 and 8 [claim 5]. The reference teaches the chemogenetic protein as hM4Di meeting the limitation o claim 10 [claim 1].
The reference discloses a CNO as a chemical actuator, but not the specific compounds of claim 11. Roth teaches the use of compound 21 and an alternative to CNO with equivalent potency (p. 687 C1). Roth teaches the use of hM4Di can be activated by compound 21 (p 688 C2). As such, compound 21 would have been an obvious substitution for CNO in the method of During. During further teaches that the microbubbles have a diameter of 3-4.5 microns, [0124], meeting the limitations of claim 14. The method of the reference can be used to target s[specific brain cells, and treat epilepsy [0072-0073, 0100], meeting the limitations of claim 21 and 22.
With these aspects in mind, it would have been obvious to combine the prior art. It would have been obvious to modify the disclosure of During with the components of Chu and Roth as they solve the same problem. It would have been obvious to modify During as seen in Shapiro in order to provide a range of effective treatments. One of ordinary skill in the art would have been motivated to combine the compound of Chu and Roth into the method of During in order to produce a method of treating conditions of the nervous system directly in the brain.
Allowable Subject Matter
Claims 20 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 MICAH PAUL YOUNG whose telephone number is (571)272-0608. The examiner can normally be reached Monday through Friday, 9:00 am to 5:30 pm.
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, Michael Hartley can be reached at 5712720616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MICAH PAUL YOUNG/Primary Examiner, Art Unit 1618