DETAILED ACTION
This action is in reply to papers filed 7/28/2023. Claims 1-6 are pending and examined herein.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240076619A1, Published 3/7/2024.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1e refers to the immature cardiomyocyte population that was not exposed to a compound as “the other cardiomyocyte population”. For the purposes of clarity, Examiner suggests Applicant amend the claims to recite a first population of immature cardiomyocytes and a second population of immature cardiomyocytes.
Appropriate correction is required.
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 1 and 3 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 preamble of claim 1 is drawn to a method of characterizing an effect of a compound on cardiomyocyte beating. However, step e of claim 1 is drawn to characterizing the compound as further driving maturation if the population with compound addition functionally matures before the other cardiomyocyte population. In essence, the preamble of claim 1 describes a screening process to determine the effect of a compound; whereas, step e of claim 1 requires a specific effect of that compound. This is confusing. This is because the objective of the claim, recited in the preamble, is not congruent with step e of claim 1. Clarification is requested.
Claim 3 is drawn to “..wherein the immature cardiomyocytes are cultured until beating is synchronized, further wherein if the beating is not synchronized, the method further comprises electrically pacing the cardiomyocytes until cardiomyocyte beating is synchronized.”
When taken with independent claim 1, the metes and bounds of claim 3 are unclear. This is because, while claim 1b recites a step of culturing, this step is performed before step d of claim 1, which requires electrically pacing of the cardiomyocytes. Nor is there a requirement for the cardiomyocytes to be synchronized in claim 1b. Moreover, claim 3 fails to acknowledge a step of adding a compound suspected of having an effect on cardiomyocyte maturation- a step required before the step of electrically pacing the cardiomyocytes in claim 1d. Therefore, it is wholly unclear how the step of culturing in claim 3 relates to the independent claim.
Appropriate correction is required.
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 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.
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 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Miklas et al. (WO2015061907A1, Published 5/7/2015; Ref. 3 in IDS filed 12/11/2023) in view of Li et al. (PgPub US20080089874A1, Published 4/17/2008 ).
Claim interpretation: In view of the 112 (b) rejection above, claim 1 step e is interpreted to be an optional step. This is because the claim recites, inter alia, “characterizing the compound as further driving maturation if the population with compound….”. Examiner’s emphasis. This recitation is not interpreted to be a requirement of the claim.
Miklas teaches that it is well accepted that some human stem cell lines are more cardiomyogenic than others and these differences could also be related to the maturity of the produced cells (Pg. 99, para. 677). Towards this end, Miklas teaches a device for, inter alia, culturing immature cardiomyocytes to maturity (Pg. 111, para. 734). Miklas teaches the device could be used for testing the efficacy and safety of experimental pharmacologic agents (Pg. 112, para. 739).
Miklas teaches the device to be a ‘Biorod’. The Biorod comprises a microwell or microchamber and a pair of grooves that intersect the microchamber in a generally perpendicular arrangement, wherein the microchamber is adapted for growing (i.e. culturing) (as in claim 1a, in-part) cells and/or tissue and may be seeded with cells of a desired tissue. Miklas teaches the grooves are adapted for receiving a pair of polymer wires such that the polymer wires when placed in the grooves traverse the open space of the microchamber. Miklas teaches the polymer wires are deflectable, deformable, bendable, or the like, which can further configured to allow the measurement of contractile forces exerted by the tissue strand on the polymer wires. For example, Miklas teaches the biorod may be configured where one of the wires is deflectable, deformable, bendable, or the like and another wire is rigid. In this manner, contractile activity can be monitored (as in claim 1a, in-part) and/or measured based on the movement of the flexible wire (Pg. 110-111, para. 733). At Pg. 111, para. 734, Miklas adds that the microwells may be configured with two electrodes (at the terminal ends of the microchannel) for stimulating (i.e. pacing) (as in claim 1a, in-part) cardiac cells.
In a use example, Miklas teaches embryoid bodies (EBs) were differentiated to the cardiovascular lineage and disassociated. hESC derived cardiomyocytes (as in claim 2) were suspended in a collagen-based gel. Suspended cardiomyocytes were then seeded into the cell culture channel of the Biorod. After 30 min incubation at 37 °C to induce the gelation, appropriate media were added. After seeding, cells were kept in culture for 7 days to allow collagen matrix remodeling and assembly around the wires (as in claim 1b, in-part). Cardiac tissue strands were kept in culture for up to 21 days with media change every 2-3 days. Miklas adds that the tissue strands should be kept in culture for at least 2 weeks to allow for maturation (Pg. 114, para. 750-752).
For validation of electrical stimulation in tissue strands cultivated using the Biorod device, electrical stimulation was applied to tissue using a similar setup as in the investigation of the device of Example 1 (Pg. 115, para. 754). Example 1 teaches tissue strands were placed perpendicular to the electrodes and were submitted to electrical stimulation (rectangular (as in claim 4), biphasic, 1 ms, 3-4 V/cm) (Pg. 82, para. 600). The pacing frequency started at 1 Hz and increased gradually and daily to 6 Hz throughout the week (1, 1.83, 2.66, 3.49, 4.82, 5.15 and 6 Hz, daily frequencies) (as in claim 5). Additional 1 week of culture with 1 Hz electrical pacing was continued to leave enough time for tissue maturation and short- or long-term drug testing experiment (as in claim 1c) (Pg. 115, para.754). Miklas teaches the drugs will be assayed for their ability to accelerate cardiac regeneration or improve contractile properties (~ effect on cardiomyocyte maturation) (Pg. 73 ,para. 571). Continuing, Miklas teaches FIG. 42B shows force per cross-section calculated from deflection at day 21 (end point assessment) with pacing frequency from 0.5Hz to 3Hz. After normalizing to forces generated at 0.5Hz, FIG. 42B showed positive force -frequency relationship (as in claim 6, in-part) (Pg. 117, para. 762). Based on these teachings, it is reasonable to conclude that immature cardiomyocytes would have a negative force-frequence relationship (as further in claim 6).
However, Miklas fails to teach (1) culturing two populations of immature cardiomyocytes (as further in claim 1b); (2) electrically pacing the two populations of immature cardiomyocytes according to a pulse profile that functionally matures immature cardiomyocytes (as in claim 1d) .
Before the effective filing date of the claimed invention, Herron et al. demonstrated that purified hiPSC-CM cardiomyocytes cultured as monolayers on PDMS+matrigel achieve a high degree of electrical maturity, with average action potential propagation velocities as high as 55 cm s−1. Herron notes that it is important to note however that while hiPSC-CM cardiomyocytes are highly purified; one always encounters mixtures of different cardiomyocyte phenotypes, including atrial-like, ventricular-like and pacemaker-like myocytes (as further in claim 1b). This is reflected in FIG. 1A by the different optical action potential (AP) configurations (right) in the monolayer. Pacemaker-like cells at the site of impulse initiation undergo slow diastolic depolarization at a steady rate until the threshold potential is reached and an action potential is generated. More distally, ventricular-like APs have stable resting membrane potentials and respond to the propagating impulse with very rapid upstrokes. In FIGS. 1B and C, action potential propagation velocity and duration over electrical pacing frequencies ranging from 0.7 to 2.5 Hz were characterized. FIG. 1B shows conduction velocity restitution as one would expect with faster conduction at lower frequency (greater cycle length) of stimulation. FIG. 1C demonstrates the action potential duration restitution of mature hiPSC-CM monolayers where APD gets shorter as pacing frequency increases. Thus, the biomatrix combination of matrigel+PDMS promotes functional electrophysiological maturation of hiPSC-CMs in as little as four days (as in claim 1d). Herron teaches using a custom made software, action potential properties including, maximum diastolic potential (MDP), dV/dtmax, overshoot, action potential (AP) amplitude (as further in claim 6), take-off potential, action potential duration (APD) at 30, 50, 70, 80 and 90% of repolarization were analyzed by calculating the mean values from 10 stable APs in each region (Pg. 6, para. 68; Pg. 8, para. 77).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A and G are applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Miklas et al., wherein Miklas teaches a system for maturing cardiomyocytes, wherein said system comprises a pair electrodes for stimulating immature cardiomyocytes, with the teachings of Herron et al., wherein Herron demonstrated that populations of atrial-like, ventricular-like and pacemaker-like myocytes cardiomyocytes cultured as monolayers on PDMS+matrigel achieve a high degree of electrical maturity. That is, one of ordinary skill in the art would have found it prima facie obvious to modify the system of Miklas to include distinct cardiomyocyte cell populations, as set forth in Herron. One of ordinary skill in the art would have been motivated to modify the teachings of Miklas in order to distinguish a chamber-specific difference in the maturation effect of the BioRod system on atrial-like, ventricular-like and pacemaker-like myocytes.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632
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