DETAILED ACTION
Applicant’s amendment to the claims in the Response filed on 01/15/2026, adding newly presented limitations and materially changing the scope of the claims, is acknowledged.
The objection to the Specification is withdrawn in view of the Substitute Specification filed on 01/15/2026.
The objections to the claims are withdrawn in view of Applicant’s amendment to the claims in the Response filed on 01/15/2026.
The rejection of record under 35 U.S.C. § 112(b) is maintained and modified in view of Applicant’s amendment to the claims in the Response filed on 01/15/2026, adding newly presented limitations and materially changing the scope of the claims, as set forth below.
The rejection of record under 35 U.S.C. § 112(a) is withdrawn in view of Applicant’s amendment to the claims in the Response filed on 01/15/2026.
The rejection of record under 35 U.S.C. § 102(a) is withdrawn in view of Applicant’s amendment to the claims in the Response filed on 01/15/2026.
The rejection of record of record under 35 U.S.C. § 103 is maintained and modified in view of Applicant’s amendment to the claims in the Response filed on 01/15/2026, adding newly presented limitations and materially changing the scope of the claims, as set forth below.
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 10-12 and 28 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.
Instant claim 10 recites “the method further comprises a step of polarization of the macrophages produced in step (a) into M1-like or M2-like macrophages. Instant claim 1 has been amended to recite, inter alia, that “the method lasts no more than 5 days.” It is unclear from this amendment if the polarization step must occur within the 5 days since the “method lasts no more than 5 days,” or if polarization occurs after the 5-day incubation with M-CSF or GM-CSF. Instant claim 1 does not limit step (a) to 5 days, but, rather the entire method to 5 days. This is problematic since the macrophages must first be produced by monocyte differentiation before subsequent polarization, and the Specification only demonstrates polarization of day5 hMDMs comparing them to day7 hMDMs (see FIGs 5, 7; ¶¶ 0294-0296, as published). The dependent claims do not additional clarity and, therefore, are also indefinite. For purposes of compact prosecution and applying prior art, the instant claims were interpreted herein consistent with the Specification to require polarization after culturing monocytes for 3-5 days to produce macrophages in step (a).
Instant claim 28 recites “the medium contains M-CSF at a concentration of between 25 and 200ng/mL.” It is unclear if “25” means 25 ng/mL or a lower concentration. For purposes of compact prosecution and applying prior art, instant claim 28 was interpreted to require an M-CSF concentration between 25 ng/mL and 200 ng/mL.
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
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.
Claims 1-2, 8, 13, and 27-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. (US 2007/0299095, prior art of record, hereinafter “Singh”).
Singh teaches a method for producing human monocyte derived macrophages (hMDMs) at >90% purity comprising culturing human monocytes in a medium comprising 100 ng/ml of macrophage colony stimulating factor (M-CSF) for 5 days to produce macrophages without re-feeding or replacing the medium (¶ 0531).
Singh teaches that the monocytes were plated out at “6 x 106 cells/150 cm TC dish in 15 mls media,” (¶ 0531), which appears less than the claimed density of between 1 x 106 cells/cm2 and 1 x 107 cells/cm2, as claimed. However, it would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal plating density to produce a desired yield of hMDMs, e.g., at least 20%, with a reasonable expectation of success. “[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).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Singh as applied to claims 1-2, 8, 13, and 27-28 above, and further in view of Rey-Giraud et al. (PLos ONE 7(8):1-10 (2012), prior art of record, hereinafter “Rey-Giraud”).
As discussed above, claims 1-2, 8, 13, and 27-28 were rendered prima facie obvious by the teachings of Singh. The reference does not teach a subsequent polarization step. However, Rey-Giraud teaches in-vitro generated human monocyte-derived macrophages can be subsequently polarized (M1) using LPS and IFN-γ (page 2, Materials and Methods, In vitro generation of monocyte-derived macrophages (MDM)). One of ordinary skill in the art would have been motivated to modify Singh using Rey-Giraud in order to advantageously produce M1-polorized hMDMs for downstream clinical and experimental applications with a reasonable expectation of success.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments filed 01/15/2026 have been fully considered but they are not persuasive. Applicant’s arguments are discussed to the extent they apply to the current grounds of rejection set forth above.
On page 10 of the Response, Applicant urges there is an “obvious typographical error” in Singh such that the “150 cm” (approximately 5 feet) TC dish taught by the reference is actually a standard 150 mm dish with an approximate surface area of 175 cm2, which would give an approximate seeding density of 3.4 x 104 cells/cm2. While the initial seeding density of Singh may be less than the amount claimed, as discussed above, it would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal plating density to produce a desired yield of hMDMs, e.g., at least 20%, with a reasonable expectation of success. Nothing in the Specification demonstrates the critically of the 1 x 106 cells/cm2 and 1 x 107 cells/cm2 seeding density range recited by instant claim 1, as amended, compared to the lower density taught by Singh—especially since the method taught by Singh also produces macrophages in five days.
On pages 14-15 of the Response, Applicant urges that claim 1, as amended, “requires seeding monocytes at a density that is substantially higher than that disclosed in Singh. In particular, the lower limit of the claimed seeding density range is approximately 30-fold higher than the density described in Singh. Singh contains no disclosure or suggestion of seeding monocytes at the claimed density, nor does it contemplate increasing cell density beyond the levels explicitly taught.”
As discussed above, it would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal plating density to produce a desired yield of hMDMs, e.g., at least 20%, with a reasonable expectation of success.
On page 15 of the Response, Applicant urges that the “claimed higher seeding density produces unexpected and striking technical effects.” In particular, Applicant urges that: “As described in the application (Example on page 35, "The inventive differentiation protocol leads to the production of mature, fully functional macrophages using GMP-graded cell culture bags.” This, however, is consistent with Singh alone or in combination with Rey-Giraud, which, as discussed, would also produce mature, fully functional macrophages. Moreover, the claims do not require the use of GMP-graded cell culture bags.
Applicant further cites to instant FIGs. 6 and 7 and urges “that seeding monocytes at the claimed densities results in significantly improved macrophage yield and viability.” The data presented in FIGs. 6 and 7, while fully considered, was not found persuasive. The cells density in FIGs. 6 and 7 is limited to 1 x 106, 2 x 106, or 3 x 106 cells/cm2. In contrast, claim 1 recites a density of 1 x 106 to 1 x 107 cells/cm2. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Moreover, the figures do not compare yield or viability to lower densities. The data does not demonstrate that the claimed range produces better, worse, or equivalent yield/viability compared to lower or higher densities. FIGs.7A, e.g., demonstrates a predicable, linear increase in yield with increasing density with FIGs.7B suggesting no real change in viability, which is consistent with routine optimization.
On page 16 of the Response, Applicant urges that “the skilled person's common general knowledge would lead them away from modifying Singh into seeding at such a higher density, particularly in a method in which no replacement or re-feeding of the medium takes place.” Applicant’s offers no evidence to support “the skilled person’s common general knowledge,” and, as such, Applicant’s constitutes unsubstantiated attorney argument. Arguments presented by Applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).
Solely to rebut Applicant’s position, Macleod et al. (Cancer Cell Culture, Vol. 88, Ch. 2 (2004)) evidences that common problems associated with cell culture, including poor growth in culture and high pH, can be solved by increasing cell density (Table 1: Common Problems Associated With Cell Culture).
Applicant’s remaining arguments were fully considered, but are moot in view of the current grounds of rejection set forth 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 THOMAS J VISONE whose telephone number is (571)270-0684. The examiner can normally be reached Monday-Thursday, 8:30 AM to 6:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Yvonne Eyler can be reached at (571) 272-1200. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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