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 .
Claims 1-30 have been cancelled. Claims 31-45 have been newly added.
Applicant's arguments filed 12/15/2025 have been fully considered but they are not persuasive.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 31-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 31-45 are not original claims. They were added by amendment on 12/15/2025. Claim 31 is the only independent claim. Basis is not seen for this claim.
New claim 31 recites:
A method of evaluating a product selected from an amnion-derived product (ADP) or a conditioned medium generated from the ADP, the method comprising:
(a) contacting a test system comprising synovial cell line in vitro with IL-1β, TNF-α, or a combination of both IL-1β and TNF-α, to activate the test system line to produce a pro-inflammatory mediator selected from the group consisting of IL-1α, IL-1β; TNF-α, IL-6, leukemia inhibitory factor, oncostatin-M; IL-8, IL-17, IL-18, MMP-1, MMP-2, MMP-3, MMP-90, MMP-13, and a combination of two or more of the foregoing;
(b) adding said product to said test system and incubating them for a period of time;
(c) determining a first concentration of said pro-inflammatory mediator produced by the test system after step (b);
(d) determining a second concentration of said pro-inflammatory mediator produced in a control in which said product has not been added to said test system in vitro; and
(e) comparing the first concentration to the second concentration to determine whether said product stimulates or inhibits production of the pro-inflammatory mediator in said test system.
Basis for “to activate the test system line to produce a pro-inflammatory mediator selected from…and a combination of two or more of the foregoing” is not seen. There is no basis for combinations of two or more. In addition, the remaining steps of the claim discuss concentrations of a single pro-inflammatory mediator (steps (c), (d), (e)) and not combinations of two or more. There is no basis for determining concentrations of multiple mediators simultaneously and determining stimulation of inhibition of pro-inflammatory mediators simultaneously. The claim has no basis.
Basis for claims 33-35 was stated to be on page 7, lines 16-20, of the 6/29/2021 substitute specification. This is not agreed with. The limitations in these claims differ from the disclosure in these lines and in original claim 10. The claims constitute new matter.
Basis for claims 36-37 was stated to be on page 8, lines 8-18, of the 6/29/2021 substitute specification. This is not agreed with. The limitations in these claims differ from the disclosure in these lines and in original claim 20. The claims constitute new matter.
The claims constitute new matter.
Claims 36-37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 36 is directed to a method for determining, prior to administration of a product to a subject, whether administration of the product to the subject is likely to produce an anti-inflammatory effect in the subject. Claim 36 sets forth no steps by which this determination is made. Claim 36 is not enabled as it lacks critical steps.
Claim 37 depends upon claim 36. Claim 37 is directed to the method of claim 36, comprising: comparing the extent to which the product stimulates or inhibits the production of the pro-inflammatory mediator in said synoviocyte cell line to a threshold value; and determining that administration of the product to the subject is likely to produce an anti-inflammatory effect in the subject if the extent to which said ADP stimulates or inhibits the production of the pro- inflammatory mediator in said synoviocyte cell line is equal to or greater than the threshold value. This method is not enabled, particularly for combinations of two or more pro-inflammatory mediators. The specification does not provide any threshold values, particularly for all pro-inflammatory mediators in claim 31. In particular, the claim lacks critical steps where multiple mediators are involved. For example, if one mediator is less than the threshold value and a second mediator is equal to or greater than the threshold value, it is unknown whether administration of the product to the subject is likely to produce an anti-inflammatory effect in the subject. The specification does not disclose how to make these determinations when multiple mediators are involved.
Example 1 discloses experiments using SW982 cells in culture. The SW982 cells are incubated with the activating factors IL1β and TNF-α. Differences in low passage (new cells) and high passage (old cells) cells as well as differences between treatment with assay medium (AM) alone or treatment with assay medium with activating factor were evaluated. Different CO2 conditions was evaluated. When culture media was exchanged for fresh media, some experiments added AM with activating factors in 100% or 50% amniotic suspension allograft conditioned media (ASA CM).
Example 2 also discloses the effects of dosing SW982 cells in culture with the activating factors IL1β and TNF-α.
TNF-α levels were determined. Due to the preserved TNF-α reduction trends, the larger differences between the assay media and activating factor-alone groups, the reduction as a result of CM treatment groups, and the persistence/increase of TNF-a levels, it was determined that the use of 10 ng/mL of TNF-a with the SW982 cells was ideal.
Example 3 investigated the repeatability of the potency assay using a pooled positive control (PPC) and an ASA (NuCel) CM from a commercial lot. was exchanged for fresh media. SW982 cells received either AM alone, AM with activating factor (IL- 18 and TNF-a), or AM with activating factor in 100% or 50% PPC CM or ASA CM. was exchanged for fresh media. The SW982 cells themselves are producing TNF-a in excess of what the activating factor is delivering within each condition. Culture supernatants were collected for analysis of TNF-α protein production. The results were normalized to their respective inflammation alone control values. Treatment with ASA CM and PPC CM saw the preservation of the decrease in TNF-α levels. See Figure 7.
Example 4 tested SW982 cell in culture with ASA CM generated from two clinical lots (TA1 and TA2) with PPC CM as a comparison. Culture supernatants were collected for analysis of TNF-α protein production. The SW982 cells themselves are producing TNF-a in excess of what the activating factor is delivering within each condition. In order to evaluate a single reportable metric for potency that could be used to compare relative potency between different experiments, percent reduction in TNF-α readouts at various doses were normalized to the PPC CM at the same dose to report relative potency at each dose and then averaged for a single readout.
Example 5 used an in vitro model of OA using human fibroblast-like synoviocytes (HFLS, a human primary cell line from synovial tissue) and placing the cells under an inflammatory stimulus (i.e. the activating factors IL1β and TNF-α). The supernatants were assayed for IL-1β, TNF-α, and IL-1Ra using ELISA. Treatment with ASA resulted in significant decreases in the pro-inflammatory cytokines, TNF-α and IL-1β. Figure 15A-B. Treatment with ASA resulted in a significant increase in the anti-inflammatory IL-1ra concentration. See Figure 15C.
These experiments were repeated using HIG-82 cells (spontaneously immortalized rabbit synoviocytes that retain the activatable phenotype of primary rabbit synoviocyte cultures) and SW982 cells. See Figures 16-17. There was variability among the different experiments and variability among the 10 lots of ASA. See Figure 18.
Example 6 discloses experiments using primary bone marrow-derived MSCs (bmMSCs) and hTERT immortalized adMSCs. Treatment of hTERT-adMSCs and bmMSCs with ASA CM following priming with IL-1β and TNF-α resulted in significant decreases in TNF-α as shown in Figure 19A-B.
In In re Wands (8 USPQ2d 1400 (CAFC 1988)) the CAFC considered the issue of enablement in molecular biology. The CAFC summarized eight factors to be considered in a determination of "undue experimentation." These factors include: (a) the quantity of experimentation necessary; (b) the amount of direction or guidance presented; (c) the presence or absence of working examples; (d) the nature of the invention; (e) the state of the prior art; (f) the relative skill of those in the art; (g) the predictability of the art; and (h) the breadth of the claims.
With respect to claims 36-37, none of the examples in the specification provides a threshold value and compares the threshold value with the extent to which the product stimulates or inhibits the production of the pro-inflammatory mediator in the synoviocyte cell line. There is no example that determines that when this extent is equal to or greater than the threshold value the anti-inflammatory effect is likely to be produced in a subject. There are no examples where a determination, prior to administration of a product to a subject, is made as to whether administration of the product to the subject is likely to produce an anti-inflammatory effect in the subject. None of the in vitro culture experiments is tied to or disclosed as extrapolating to results or predicting results an in vivo situation where the product or substance derived from the product of the assay is administered to a subject.
The specification does not disclose the determination of any thresholds that could be used as cut-offs or predictors. That is, there are no working examples of the claimed methods.
It is not considered to be so predictable that one of ordinary skill in the art could have practiced the claimed method without undue experimentation, particularly with respect to repeatability and reproducibility.
The claims are not enabled by the specification.
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 31-45 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 recitation in claim 31 “to activate the test system line” lacks antecedent basis in the claim and appears to be a word processing error. The test system comprises a synovial cell line. It appears that either the test system or the synovial cell line should have been referenced. The claim is confusing.
Claim 31 is indefinite in reciting an “amnion-derived product (ADP) or a conditioned medium generated from the ADP.” Basis for this limitation was stated to be on page 9, lines 12-16 and page 15, lines 15-17, of the 6/29/2021 substitute specification. This is not agreed with. Page 9, lines 12-14, and page 15, lines 15-17, do not discuss amnion derived products. It appears applicant may have intended page 9, lines 15-16. The specification does not use the acronym ADP. The specification does not provide a limiting definition for an amnion-derived product. The claims are not limited to the disclosed example of an amnion suspension allograft (ASA). It is not known what “derived” implies with respect to an amnion and the identity of the claimed amnion-derived product. For example, it is unknown what chemical or biological manipulations and/or reactions are encompassed by “derived.” While a conditioned medium (CM) can be derived or generated from an amnion suspension allograft (ASA), the claims make clear that the amnion-derived product is a separate product from the conditioned medium and is not the amnion-derived product itself. (See also claim 39.) The metes and bounds of the claim cannot be determined.
Claim 31 is confusing in referring to combinations of two or more pro-inflammatory mediators in part (a) while referring to singular pro-inflammatory mediators in parts (c), (d), and (e). See also dependent claims where only a singular pro-inflammatory mediator is referenced.
Claim 32 is indefinite. Basis for claim 32 was stated to be on page 9, lines 17-20, of the 6/29/2021 substitute specification. This is not agreed with. This section discusses conditioned medium. It appears applicant may have intended page 9, lines 15-16. However, these lines in the specification do not provide a limiting definition of an “activatable phenotype.” The claims are not limited to the disclosed example of the SW982 cell line. That is, it is not clearly or necessarily a transformed synovial cell line with the ability to produce the pro-inflammatory mediators in claim 31. The metes and bounds of the claim cannot be determined. Note that no other transformed human synovial cell lines having this property are identified. No other activatable phenotypes are disclosed.
Claim 33 is confusing in reciting “further comprising measuring an extent to which said product stimulates or inhibits.” Claim 33 depends upon claim 31. Claim 31 already requires comparing the difference in concentrations to determine whether the ADP stimulated or inhibits production of the pro-inflammatory mediator in step (e). It is unclear what specific additional measurements or additional steps are being performed in claim 33.
Claim 34 is indefinite in failing to identify what the standard value is in the context of claims 31 and 33. Claim 35 recites adding a standard without identifying what the standard is. It appears that the calculated standard value of claim 35 is the concentration of something. If it is not the concentration, then the claim is unclear as to what further “calculations” must be made. The claims are incomplete and confusing. It is noted that the comparison in claim 34 and dependent claim 35 is not used in any way with respect to the method of claim 31.
Claim 36 is confusing in reciting “prior to administration of the product to a subject.” Claim 31 is method of evaluating and not a method of administering a product to a patient or a method of treating a patient. It is unclear if claim 36 requires administration to a subject. In addition, the phrase “is likely to” in the claim is a relative phrase which renders the claim indefinite. The phrase “is likely to” 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. This claim sets forth no steps for making this determination. This claim is incomplete and confusing.
Claim 43 lacks antecedent basis in claim 31 for a transformed human synovial cell line.
Proposed claims 31-35 provided in the 7/31/2025 Office action remain allowable. Basis for these claims is found in the figures, the examples, and the original 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 MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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