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 .
Status of Claims
In response filed June 16, 2025, Applicant has amended claims 1, 9, 12, 20, and 55-56, and have canceled claims 2, 5-8, 11, 13, 16-19, and 22-54 have been canceled.
Currently, claims 1, 3-4, 9-10, 12, 14-15, 20-21 and 55-56 are currently being examined.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Declarations under 37 CFR 1.132
The declarations under 37 CFR 1.132 filed on 6/16/2025 by Dr. Breanna Shalyn Borys, is sufficient to overcome the obviousness rejection of claims 1, 3-4, 9-10, 12, 14-15, 20-21 and 55-56 based on Borys, Breanna S., et al. (Biochemical Engineering Journal 133: 157-167; cited IDS 08/04/2023, published 2018 – prior art of record). Specifically, the filed declarations disqualify the disclosure of Borys as prior art because it was made by the inventor. Further, the declarations state that the publication of Borys discloses that the volume average energy dissipation rate should be maintained constant on scale up rather than maintaining the constant distribution of actual energy dissipation rates on a scale-up beyond ten milliliters as disclosed in the claims.
The declarations under 37 CFR 1.132 filed on 6/16/2025 and 6/17/2025 by Mr. Peter Gray, Dr. Mathew Croughan, Dr. Michael Kallos, and Dr. Breanna Shalyn Borys are sufficient to overcome the obviousness rejection of claims 1, 3-4, 9-10, 12, 14-15, 20-21 and 55-56 based upon Johnson, et al (Biotechnology progress 30.3: 760-764; published 2014 - prior art of record), in view of Jung et al. (Bioreactors for Stem Cell Expansion and Differentiation. CRC Press. 201-242; published 2018 – prior art of record), Sousa et al (Biotechnol Prog.;31:1600-1612; published 2015 - prior art of record), and Delafosse, et al. (Chemical Engineering Science 66.8: 1728-1737; published 2011 - prior art of record). The declarations disclose that the prior art of Jung is silent regarding the agitation rates and Delafosse teaches that while operating at 50 rpm, the mean Kolmogorov scale is greater than the microcarrier diameter, which is desirable, but the actual Kolmogorov scales located immediately adjacent to the impeller discharge zone are much larger such that the cells would be damaged. Therefore, a person of ordinary skill in the art would not have expected that the distributions did not just shift to higher volume average values (which occurs when increasing agitation rate alone), rather the shape of the distribution of the EDR rates changed entirely. Additionally, all of the declarations included statements of long-felt but unsolved need citing Huang (2020), which discloses attempts to scale up ten milliliters using a range of different bioreactor designs and discloses that the field still requires a process for large scale-up of pluripotent stem cell (PSC) aggregate cultures.
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, 3-4, 9-10, 12, 14-15, 20-21 and 55-56 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.
This is a new rejection necessitated by amendment to the claims. However, any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Claims 1 and 12 recite: “A method of scaling production of cells derived from humans or animals grown on microcarriers or as cell aggregates in a suspension-based bioreactor.”
Claims 1 and 12, recite a broad recitation of “determining a target average energy dissipation rate (EDR) of turbulent eddies within a suspension including cells,” and then the claim recites “wherein the target average EDR is between 0.0003 m2/s3 and 0.0015 m2/s3”, which is a narrower statement of the limitation. Therefore, the claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the instant case, it is unclear what is “a target average” and if it is the average energy dissipation rate (EDR) of turbulent eddies or if it is the target average EDR in a small or large scale bioreactor and if the suspension is considered to be more than just comprising of cells or if the suspension’s volume comprises specific culture media.
Claims 1 and 12, recite the phrase “target”, which is a relative term and therefore undefined because is not apparent to one of ordinary skill in the art as to what EDR comparison is being made to obtain the “target average EDR of turbulent eddies within a suspension of cells”. The target value is unclear it is not comparing step as to what the “target value” is being compared to or measured against. Therefore, the instant claim fails to interrelate essential steps of the invention as defined by Applicant(s) in the specification. Note MPEP 2172.01 states that such essential matter may include missing elements, steps or necessary structural cooperative relationships of elements described by the applicant(s) as necessary to practice the invention. As such, the claim is indefinite because the structural elements of first determining a target EDR and then setting an agitation rate, which results in actuating a mixer are not apparent. Thus, the missing essential step of the claims 1 and 12 is having the step of an equation, device or computational fluid dynamics modeling to determine the target average energy dissipation rate of the turbulent eddies within the suspension.
Claims 1 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01.
The declarations filed on 6/16/2025 and 6/17/2025 are evidence that computational fluid dynamic CFD modeling was present in degerming the target energy dissipation rate (EDR) of turbulent eddies. For example, Dr. Croughan declared that “a person of ordinary skill in the art understands that determining an average EDR can be accomplished through multiple mathematical or experimental methods. Average EDR can be derived as an output from computational fluid dynamic CFD modeling, as is the case for the data presented in the patent application” (page 3). Further, Mr. Gray states that “a person having ordinary skill in the art would understand that by consulting FIG. 26A of the application, an average EDR can be determined for the various bioreactors identified where the volume and agitation rate for that bioreactor are known. 10. A person of ordinary skill understands that the data in Fig. 26A is exemplary and that computational fluid dynamics (CFO) can be utilized to generate unlimited data points for all possible volumes and agitation rates of anticipated bioreactor geometries or scales.
Therefore, the omitted structural cooperative relationships are: “computational fluid dynamics (CFD)) that determined by physical mixing studies, power measurements, and computational fluid dynamics (CFD) analyses, for optimum and scalable production of therapeutic cells grown on microcarriers or as cell aggregates in a suspension-based bioreactor”(see e.g. Specification para. 127).
Claims 1 and 12, recite the phrase “the large scale agitation rate being directly dependent on the small scale agitation rate;” (line 17).
MPEP 2173.05(g) recites “Notwithstanding the permissible instances, the use of functional language in a claim may fail “to provide a clear-cut indication of the scope of the subject matter embraced by the claim” and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. Halliburton Energy Servs., Inc. v. M-I LLC, 514 F.3d 1244, 1255, 85 USPQ2d 1654, 1663 (Fed. Cir. 2008) (noting that the Supreme Court explained that a vice of functional claiming occurs “when the inventor is painstaking when he recites what has already been seen, and then uses conveniently functional language at the exact point of novelty”) (quoting General Elec. Co. v. Wabash Appliance Corp., 304 U.S. 364, 371 (1938)); see also United Carbon Co. v. Binney & Smith Co., 317 U.S. 228, 234, 55 USPQ 381 (1942) (holding indefinite claims that recited substantially pure carbon black “in the form of commercially uniform, comparatively small, rounded smooth aggregates having a spongy or porous exterior”).
The MPEP 217.05 states “A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite. See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989).
In the instant case, the nature of the “dependent” relationship is unclear. There is no structure in the claim that defines what the nature is of the “dependable” relationship. Thus, the claim limitation is indefinite because it is not clear how to have “the large scale agitation rate” be dependent upon “the small scale agitation rate” when the object that is being dependent upon is variable. Additionally, the terms “a small scale agitation rate” and “a large scale agitation rate” in claim 1 and 12 is a relative term which renders the claim indefinite. The terms “small” and “large” for the agitation rate is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The terms “small” and “large” are referred to throughout the claim for the mixer scale and the agitation rate of the bioreactor. However, it is unclear what is considered small and large for a mixer’s agitation rate in the bioreactor. Therefore, there are no metes and bounds to the limitation and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claims 1 and 12, the last step of actuating the mixer recites the phrase “the plurality of actual EDR data points.” However, the phrase “data points” are generally referring to a piece of information or identifiable element in a dataset from experiments that have already happened. Therefore, the last step of actuating is unclear because the step is directed to causing the mixer to work but the claim refers to the EDR as information that has already happened. Thus, a person of ordinary skill in the art would be confused as to what the phrase “actual” means in the claim limitation of “the plurality of actual EDR data points” and if it is referring to an EDR that is from a physical experiment or a computer modeling device.
Regarding claims 1 and 12, the claim recites “wherein a magnitude of at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 97% of the plurality of actual EDR data points within the volume of the suspension in the large scale bioreactor is less than 0.0015 m2/s3.” A person of ordinary skill in the art would not know what “magnitude” the claim limitation is referring to in regards of percentages. The term “magnitude” generally refers to a measurement or quantity, but the claim is referring to an EDR rate. Therefore, it is unclear to a person of ordinary skill in the art if the magnitude is referring to the actual EDR of turbulent eddies or a plurality of EDR data points.
The phrase “approximately equal” in claim 1 and 12 (see e.g. lin. 24) is a relative term which renders the claim indefinite. The term “approximately equal” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. However, in another case, the court held that claims reciting "at least about" (comparable to “at least approximately”) were invalid for indefiniteness where there was close prior art and there was nothing in the specification, prosecution history, or the prior art to provide any indication as to what range of specific activity is covered by the term "about." Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991). MPEP 2173.05(b). Therefore, there are no metes and bounds to the limitation and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claims 9 and 20, recites “wherein depositing a suspension including cells into the large scale bioreactor comprises depositing pluripotent stem cells (PSCs) into the large scale bioreactor, and wherein actuating the large scale mixer further comprises causing the PSCs to form essentially spherical cell aggregates statistically similar in diameter with a coefficient of variation less than 20%”.
There is insufficient antecedent basis for the limitation of a “spherical cell” aggregates and “statistically similar diameter” in the claim. Claim 1 and 12 previously recite “A method of scaling production of cells derived from humans or animals grown on microcarriers or as cell aggregates in a suspension-based bioreactor.” Therefore, it is unclear if the PSC are the spherical cell aggregates and how they are being obtained. Furthermore, the diameter of the spherical cell aggregates is not disclosed in units or in the claims. Therefore, it is unclear to a person of ordinary skill in the art as to what size diameter would be sufficient to have “a coefficient of variation less than 20%.”
Furthermore, claims 3-4, 9-10, 14-15, 20-21 and 55-56 are rejected because they depend from claims 1 and 12, and do not remedy the deficiencies above. Appropriate correction is required.
Response to Traversal:
Applicant asserts that “independent claims 1 and 12 are amended to define "small" scale as having a working volume that is less than or equal to 1 L and "large" scale as having a working volume that is greater than 1 L. Moreover, the phrase "at least approximately" has been removed from the claims” (Remarks, Page 9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants arguments, the Examiner appreciates the amendment of defining the "small" scale as having a working volume that is less than or equal to 1 L and "large" scale as having a working volume that is greater than 1 L. However, the claim has not been amended for defining the “small” or “large” agitation rate and renders the claim indefinite, as discussed above.
Conclusion
No claim is 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.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
Prosecution Insights