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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/15/2025 has been entered.
Response to Amendment
Applicant's amendment and argument filed 12/15/2025, in response to the final rejection, are acknowledged and have been fully considered. Any previous rejection or objection not mentioned herein is withdrawn.
Claims 21-26 are being examined on the merits.
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 21-26 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 phrases “at least about” in claim 21 to describe concentrations are unclear. Is it at least or is it about, which encompasses less than the amount claimed? The broad range together with a narrow range is indefinite.
Claims dependent on the rejected claim are rejected for failing to cure the indefiniteness.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over Galea and Irina Brokhman (US20170296583A1). This rejection is maintained with modifications due to the arguments filed on 12/15/2025.
Galea discloses “a method of treating a mammal suffering from damaged and/or injured connective tissues, chronic tendinosis, chronic muscle tears and/or chronic degenerative joint conditions and skin inflammatory disorders, the method comprising the following steps: preparing an anti-inflammatory/anti-catabolic component an autologous composition comprising IL-1ra and TIMPs, the step of preparing the anti-inflammatory/anti-catabolic component comprising the following steps: collecting blood from the mammal; delivering the blood to a tube; incubating the blood at a temperature of from about 37° C. to about 39° C. for about 24 hours; centrifuging the blood to separate the blood into a supernatant component and a cellular fraction; and collecting the supernatant component of the anti-inflammatory/anti-catabolic component and preparing a regenerative component of the autologous composition comprising the following steps: collecting blood from the mammal; delivering the blood to a tube in the presence of about 4% citric acid;
centrifuging the blood to separate a platelet rich plasma component from a whole blood; and
collecting the platelet rich plasma component; mixing the supernatant component with the platelet rich plasma component to provide the autologous composition; and administering the autologous composition to the mammal (see claim 33).
Galea teaches that the presence of increased MMP9 concentration in the autologous bioactive composition may result in an adverse effect manifestation during the patient treatment process. It is, therefore, desired to selectively eliminate this negative component. The presence of the anticoagulant, sodium citrate, significantly down-regulates MMP9 release by human blood leukocytes (see claim 48 and 0149) and Galea teaches admixing the blood with an anticoagulant (sodium citrate).
Galea further teaches “It is further surprising that in producing the anti-inflammatory/anti-catabolic component hereof, the addition of sodium citrate prior to incubating a patient's blood at a temperature of from about 37° C. to about 39° C. for about 24 hours, prevents an increased level of pathological molecular agents that have a catabolic effect on joints such as MMP9, IL-1β and TNF-α, but yet does not lead to a significantly decreased level of anti-catabolic and regenerative agents such as TIMPs, IL-1ra and PDGF” (see 0091).
Furthermore, Galea describes wherein human serum samples were exposed to incubation conditions at different time points. And describes that such activation is achieved by contact between blood cells and the internal surfaces of the collection tubes through the use of an agitation process. By increasing the internal surface area exposed to the cellular component, the cell activation process and bioactive molecule secretion can be maximized (see 0103).
Galea teaches “Preferably, the incubation of blood is in the presence of 0.64-0.72 mM Ca++ to facilitate IL-1ra production” (see 0095). Preferably, incubation is carried out in static conditions as shown in FIG. 1 (see 0094).
Regarding claims 21-23, Galea discloses that samples were incubated for 3.5 hours, 7 hours and 24 hours (see 0104) and this indicates a time wherein the samples are incubated for at least the time of the instantly claimed parameters.
Regarding claim 24, Galea discloses wherein the sodium citrate is 4% (see 0007 and 0012).
Regarding claim 25-26, Galea discloses that delivering the blood to a tube including a quantity of about 4% citric acid comprises providing a ratio of 9.5 parts of whole blood: 0.5 parts of 4% citric acid (see claim 43).
Regarding claim 26, Galea discloses the ratio is preferably, in 9.5 parts of whole blood (9.5 cc): 0.5 (0.5 cc) of 4% citric acid ratio (see 0099).
Galea teaches using Ca++ to achieve the number of IL1-ra levels at a concentration of at least 600 pg/ml (see figure 2) and shows the concentration levels of the TIMP1 and TIMP2 to be at near 8000pg/ml and at 5000pg/ml (see figure 15), these are the active components for the composition which are optimizable for the treatment of damaged tissues and thus would have been one in which an artisan would want to increase. The prior art shows effective treatment at lower amounts and so increasing these is well within the purview of any skilled artisan. Additionally, Galea teaches “In the fifteen patients tested, an average level of TIMP2 in native serum (blood) at 0 hours of incubation was measured to be 1800±150 pg/ml. In the final product resulting from the combination of the anti-inflammatory/anti-catabolic component with the regenerative or PRP component, the average measurement for TIMP2 in native serum (blood) was 5500±360 pg/ml. This was the case, both with the addition of sodium citrate to the anti-inflammatory/anti-catabolic component and where no sodium citrate was added” (see 0146).
Therefore it would have been obvious to persons having skill in the art before the effective filing date to optimize the incubation times and the amount of anti-inflammatory/anti-catabolic component as these are optimizable parameters in creating a method of treating a mammal suffering from damaged and/or injured connective tissues, chronic tendinosis, chronic muscle tears and/or chronic degenerative joint conditions and skin inflammatory disorders. Galea teaches the instantly claimed method for such an effective treatment and indeed teaches the same method for preparing the anti-inflammatory/anti-catabolic component and teaches it being useful for the same purpose. Given Galea’s art there would have been a reasonable expectation of success in arriving at the instant invention.
Response to Arguments
Applicant's arguments filed 12/15/2025 have been fully considered but they are not persuasive. The applicant argues that Galea does not teach each and every step of what is being claimed in the instant invention, however this is not the case. Specifically Galea does not disclose, suggest, or teach preparing an anti-inflammatory/anti-catabolic component of an autologous composition wherein an admixture of blood and sodium citrate is incubated for less than about 24 hours. Galea teaches incubation times less than 24 hours using agitation (see para. 0104). Galea also teaches reasons to include sodium citrate with blood during incubation. Galea teaches that “it is further surprising that in producing the anti-inflammatory/anti-catabolic component hereof, the addition of sodium citrate prior to incubating a patient's blood at a temperature of from about 37° C. to about 39° C. for about 24 hours, prevents an increased level of pathological molecular agents that have a catabolic effect on joints such as MMP9, IL-1β and TNF-α, but yet does not lead to a significantly decreased level of anti-catabolic and regenerative agents such as TIMPs, IL-1ra and PDGF”. Therefore persons having skill in the art would indeed include sodium citrate in with the incubation of blood while preparing the anti-inflammatory/anti-catabolic composition because one would want to prevent an increase in pathological molecular agents that have a catabolic effect on joints. Additionally, sodium citrate is known in the art as an anticoagulant used during the handling and preparation of blood compositions. Galea also recognizes and teaches this; “The presence of increased MMP9 concentration in the autologous bioactive composition may result in an adverse effect manifestation during the patient treatment process. It is, therefore, desired to selectively eliminate this negative component. The presence of the anticoagulant, sodium citrate, significantly down-regulates MMP9 release by human blood leukocytes”. “Particularly, adding sodium citrate in preparing the anti-inflammatory/anti-catabolic component significantly decreased MMP9 concentration in the final product of the combination of the anti-inflammatory/anti-catabolic component and the regenerative component (thrombin-activated PRP+24 h serum)” (see 0149). Optimizing the incubation time is well within the purview of a skilled artisan. Galea recognizes this because they chart concentrations of IL1-RA versus time (see Figure 1). The active components for the treatment are the cytokines IL1-RA, TIMPs1 and TIMPs2 and the regenerative PRP. That is recognized in the art and there are ways of increasing those active components as described by Galea. Increasing Ca++, agitating the tubes in which the blood is in, using sodium citrate as an anticoagulant during incubation to prevent harmful MMP9 concentrations and for maintaining levels of beneficial cytokines and growth factors IL1-RA, TIMPs and PDGF. Therefore persons would indeed use sodium citrate as an anticoagulant and incubate with the blood for about 3.5 to about 12 hours as these are all components taught in the prior art and optimizations that would not require any undue experimentation at all. Although the prior art relied upon may not show any working examples that test for the levels of IL1-RA and TIMPs at the hours in between 3.5 and 12 hours that does not mean that these components are not obvious. One would indeed recognize reasons to do so. The art does not have to direct persons having skill in the art to add in additional tests to see if there is an increase in levels of active components at varying time points because this is what persons having skill in the art would already know to do during routine experimentation. Furthermore, it is the product being administered to the patient which is useful for treating the damaged tissues. The method for obtaining/creating that product which is being administered has been disclosed. There appears to be no difference in treatment as the amounts being administered appear to be identical. Merely trying to obtain the product sooner does not warrant a patentable distinction over the prior art as this does not appear to affect the outcome of the patient or improve the treatment. The applicant has not shown any improvement in patient outcomes over the prior art. The only argument posed by the applicant is that they believe to have found that adding sodium citrate to the blood increases IL1-RA and TIMPs at the hours in between 3.5 and 12 hours and they argue that this component is unexpected. However given the prior art it is not, because that is what the prior arts goal is, which is to increase the active components to administer to the patient. The art discusses ways in doing so and one would ultimately arrive at the exact same treatment.
The applicant shows wherein the prior art is silent on incubating the blood with sodium citrate at shorter incubation times because they do not provide any working examples wherein, they test the blood for increased growth factors at hours shorter than 24 hours. Even if the prior art does not test the blood at the hours between 3.5 to 12 hours in the presence of sodium citrate does not mean that this is not obvious and that the blood would not inherently have the same levels of cytokines and growth factors. As discussed in the MPEP “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics.")”. See also MPEP 2112.02 (at Ex Parte Novitski, and Dart cited therein) which establishes in a method of treating with a biological material that the properties need not be expressly taught in the prior art such that even reference-silent properties are inherently present, including those properties appreciated and evidenced as present only by Applicant’s own disclosure.
In this case Galea teaches the direct incubation times or at least makes them obvious because it can be appreciated that this is a component that was already done (see figure 1). Galea charts IL1-RA levels versus time because this is one of the active components used in the treatment and one which can be optimized. Galea additionally teaches why one would use sodium citrate during incubation (see above), and although did not at the time test for the presence of IL1-RA during sodium citrate incubation does not mean it was not obvious to do so and that the levels of IL1-RA would not inherently be the same as what is being argued, because those are components made obvious from the prior art.
The applicant argues that routine optimization of a result effective variable does not provide sufficient motivation when the prior art teaches against the claimed value. The applicant with this argument believes that even though time may be an optimizable parameter that the Office has not articulated why one would arrive at the specific time points being claimed/argued about 3.5 hours to about 12 hours incubation. If time is optimizable then one would test different time points. Given the prior art already does so showing time points of 3.5 hours and 7 hours, this is an obvious starting point and within the times being claimed. Therefore one would arrive directly within the time points being claimed/argued.
Conclusion
Currently no claims are allowed.
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JACOB A BOECKELMANExaminer, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655