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 .
Applicant’s amendments and arguments of August 25, 2026, are entered.
Claims 1, 3, and 16 have been amended.
No new claims have been added.
Oath/Declaration
The declaration submitted by Applicant on August 25, 2026, under 37 CFR 1.131 is acknowledged and has been considered by the examiner.
However, the declaration provided by Applicant is unpersuasive for the following reasons:
The experiment utilizes untreated, unquantified platelet rich plasma and does not establish that the composition was prepared according to the methods of claim 1 or claim 3 where both included quantification and activation, supernatant removal by centrifugation, and mixing with platelet-poor plasma before freeze drying. Furthermore, the declaration does not demonstrate the platelet-gel formation required by claim 5. With respect to claims 5-8, the reported 10% calcium chloride concentration (v/v) has not been shown to correspond to the claimed calcium concentrations expressed in % (w/v). Although the examiner acknowledges that these claims do not require platelet-gel formation and directly depend from claim 4 where it states compositions are used in colloid or liquid form. However, as stated above, the process, as stated in Applicant’s declaration, does not match the steps as claimed in claim 3 and are present in claims 6-8. Moreover, the declaration reports only a single concentration of 10% calcium chloride (v/v), whereas Claims 6 and 7 recite calcium chloride concentrations below the stated 10% (v/v) with claim 8 reciting a multitude of claimed ranges up to 10% (w/v). Based on this, Applicant has not established a sufficient nexus between the experimental data cited in the declaration and the subject matter as claimed in claims 1, 3-8. Based on this, Applicant’s declaration under 37 CFR 1.131 submitted on August 25, 2026, was not found persuasive.
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 (i.e., changing from AIA to pre-AIA ) 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.
Claims 1-10, 13-14, and 16-17 are rejected under 35 U.S.C. §103 as being unpatentable over Andia et al. [Freeze-drying of platelet-rich plasma: the quest for standardization, International Journal of Molecular Sciences, 2020], in view of Escobar et al. [Pure platelet-rich plasma and supernatant of calcium-activated P-PRP induced different phenotypes of human macrophages, Regenerative Medicine, 2018], in view of Shiga et al. [Freeze-dried human platelet-rich plasma retains activation and growth factor expression after an eight-week preservation period, Asian Spine J., 2017], in view of European Medicines Agency (Hereinafter EMA) [Guideline on the quality of water for pharmaceutical use, 2020], in view of Wermeling et al. [Osmolality of small-molecule intravenous admixtures, American Journal of Hospital Pharmacy, 1985], in view of Ralsonics Surface Engineering Solutions (Hereinafter Ralsonics) [Using sonicators in the pharma industry, 2018], in view of Meury et al. [US 2007 280959 A1].
For claim 1, Andia et al. Andia et al., discussing multiple methods for platelet rich plasma (PRP) preservation, teaches platelet containing composition comprising platelet rich plasma and platelet poor plasma (PPP) where preparing anticoagulated whole blood can be either single spun or double spun resulting in either platelet rich plasma or platelet concentrate, i.e. high purity [Figure 2]. Andia et al. further teaches that platelet pellets can be resuspended in a determined amount of platelet poor plasma for purposes of adjusting concentration. Andia et al. also discloses that activation can be either through the use of calcium chloride/thrombin or by sonication [Id.]. Additionally, Andia et al., citing Pan et al. [12], discloses that products should be calcium activated prior to freeze-drying [2.1 Lyophilized PRP preservation ¶ 3]. However, Andia et al. does not expressly teach centrifuging the PRP after activation to remove supernatant prior to mixing with PPP.
For this limitation, Escobar et al. teaches activating P-PRP with calcium chloride followed by centrifugation of the activated preparation at a specified speed and duration [P-PRP activation & S-PRP preparation ¶ 1] where the supernatant is separated and subsequently removed [Fig. 1].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Andia et al. that teaches a multitude of methods for PRP purification that is later mixed back with PPP with the teachings of Escobar et al. that discloses that the PRP, after activation with calcium chloride, is centrifuged where a supernatant is formed and the resulting supernatant is removed creating both a P-PRP, pure platelet rich plasma, and a S-PRP, supernatant of calcium active P-PRP. Based on this, there would have a been a reasonable expectation of success for a person of ordinary skill in the art since Andia et al. provided a known teaching and/or technique for to a PRP preparation with the additional teachings of Escobar et al. that demonstrates successful calcium activation followed by centrifugation and supernatant separation where PPP could then be added to the PRP mixture prior to freeze-drying. Furthermore, MPEP § 2143(I)(A) states “The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.” In the instant case, Andia et al. teaches centrifugation to obtain/concentrate platelets, adjustment/resuspension using PPP, platelet activation, and freeze drying. Escobar et al. teaches calcium chloride activation followed by centrifugation and separation of the supernatant. Each operation continues to perform its known function, i.e. activation activates the platelets, centrifugation separates the activated platelet material from supernatant, PPP adjusts/resuspends the platelet preparation, and freeze-drying preserves the resulting preparation.
For claim 2 where the platelet-containing composition is added to a form a colloid or liquid, Shiga et al. discloses two different scenarios for activation where in one example 100 microliters of calcium chloride and 100 microliters of thrombin solution are added to platelet-rich plasma where, initially, a liquid is formed prior to formation of fibrin [4. Platelet activation]. The other example includes adding buffered saline to platelet-rich plasma resulting in a liquid [5. Assessment of platelet activation via flow cytometry ¶ 1]. Furthermore, Andia et al. teaches that platelet concentrate can be resuspended where this would be understood by a person of ordinary skill in the art would mean a number of different states such as liquid suspension, colloidal mixture, semi-gel, etc. [Fig. 2]. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would combine the teachings of Andia et al. with the further teachings of Shiga et al. in order to combine a platelet rich concentrate that with platelet poor plasma to adjust concentration and further activating the platelet rich plasma composition prior to freeze drying given that Andia et al. disclosed this method in order to avoid reduced kinetics of certain growth factors. Because of this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Andia et al. that discussed the many different protocols for preserving platelet rich plasma with the further teachings of Shiga et al. that also discloses various methods for preserving platelet rich plasma compounds.
For claim 3, Andia et al. teaches preparation of platelet-containing compositions form whole blood [Fig. 2], including centrifugation to separate and obtain PRP and PPP followed by quantification/concentration of the platelet preparation [Id], resuspension or mixing the PRP concentrate with a determined amount of PPP to adjust platelet concentration, activation of the PRP using calcium chloride/thrombin, and a subsequent freeze-drying of the platelet preparation [Again, See Fig. 2, 2.1 Lyophilized PRP preservation]. Andia et al. does not expressly teach, within the sequence, adding the activator to the PRP and thereafter centrifuging the activated PRP thereby separating the supernatant prior to mixing with the PPP. However, Escobar et al. does teach this processing sequence by activating the P-PRP with calcium chloride followed by centrifugation of the activated PRP and separation of the resultant supernatant [Fig. 1]. It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Andia et al. with the additional teachings of Escobar et al. providing a known sequence of steps that involve collecting whole blood, centrifuging the whole blood to separate the PRP and PPP, activating the PRP, centrifuging the PRP and removing the supernatant as taught by Escobar et al., adding PPP back to the PRP as a diluent, followed by freeze-drying for preservation. Here, a person of ordinary skill in the art would have had a reasonable expectation of success using the teachings of Andia et al. and Escobar et al. to collect whole blood, centrifuge the collected blood for purposes of concentrating the platelet-rich plasma, activating the PRP, centrifuging the activated PRP, removing the supernatant from the centrifuged, activated PRP, diluting the PRP with PPP based on required concentration levels, and lastly, freeze-drying the platelet composition. The combination requires no change in the established function of the respective processing steps and would have predictably produced the claimed platelet-containing composition.
For claim 4 where an additive is added to the platelet-containing composition to a form a colloid or liquid, Shiga et al. discloses two different scenarios for activation where in one example 100 microliters of calcium chloride and 100 microliters of thrombin solution are added to platelet-rich plasma where, initially, a liquid is formed prior to formation of fibrin [4. Platelet activation]. The other example includes adding buffered saline to platelet-rich plasma resulting
in a liquid [5. Assessment of platelet activation via flow cytometry ¶ 1]. Furthermore, Andia et al. teaches that platelet concentrate can be resuspended where this would be understood by a person of ordinary skill in the art would mean a number of different states such as liquid suspension, colloidal mixture, semi-gel, etc. [Fig. 2]. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would combine the teachings of Andia et al. with the further teachings of Shiga et al. in order to combine a platelet rich concentrate that with platelet poor plasma to adjust concentration and further activating the platelet rich plasma composition prior to freeze drying given that Andia et al. disclosed this method in order to avoid reduced kinetics of certain growth factors. Because of this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Andia et al. that discussed the many different protocols for preserving platelet rich plasma with the further teachings of Shiga et al. that also discloses various methods for preserving platelet rich plasma compounds.
For claims 5-8 where the additive is in the range of 0.01 ~ 10% Ca2+, Shiga et al. discloses 100 microliters of calcium chloride for 10-15mL of platelet-rich plasma, the calcium chloride represents roughly 0.66 to 0.99% [4. Platelet activation ¶ 1].
For claim 9 where a gel is prepared in shape and thickness for irregular wounds or bone repair/protection, Godoi et al. discloses the use of platelet-rich plasma where it has been evaluated and established in numerous musculoskeletal conditions that include osteoarthritis, tendinopathies, and osteonecrosis, as well as stimulating wound healing in patients. Furthermore, it would have been obvious to a person of ordinary skill in the art that platelet-rich plasma compositions, e.g. gels, used for wound healing are typically molded or shaped to conform to the dimensions of the specific wound site to ensure optimal coverage and contact with the relative tissue. Such shaping would have been routine and predictable practice in the art and would be considered prima facie obvious to a skilled artisan applying platelet-rich plasma composition gels for therapeutic purposes.
For claim 10 where the additive is a solvent and the platelet composite solution is formed, Shiga et al. discloses the use where lyophilized platelet-rich plasma can be incorporated into artificial bone after being dissolved in water [Discussion ¶ 4].
For claim 13, Andia et al teaches the method of claim 3 as discussed above and further teaches quantifying and adjusting platelet concentration by centrifugation and resuspending the resulting platelet concentration in a determined volume [Fig. 2]. Additionally, Shiga et al. discusses preparation of PRP by centrifugation having a mean platelet concentration of approximately 130.0 +/- 41.1 x 104 platelets/µL which corresponds to approximately 1.3 x 109 platelets/mL [Results 1. Platelet counts]. However, Andia et al. or Shiga et al. disclose using water for injection to perform the claimed concentration adjustment. However, the EMA guidelines teach water for injection as an established pharmaceutical grade of water for the manufacture of medicinal products, including parenteral preparations, and identifies pharmaceutical water according to its intended use and required quality [4.2]. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Andia et al. and Shiga et al. that teach adjustment of concentration of platelet concentration where Shiga et al. specifically teaches successful preparation of PRP at approximately 109 platelets/mL, and the EMA guidelines establishes water for injection as a recognized pharmaceutical-grade water for preparation of medicinal products and would have resulted in a reasonable expectation of success given that water for injection is a recognized diluent used in medicinal compositions being administered to subjects.
For claim 14 where normal saline, 0.45% NaCl, 4.5% hypertonic saline, or isotonic saline is used as a substitute for water for injection, Trissel et al. teaches that 0.45% NaCl injection and water for injection are known alternative diluents for pharmaceutical preparations [Abstract]. Here, a person of ordinary skill in the art would have recognized that use of a defined pharmaceutical diluent when resuspending platelets provides controlled adjustment of platelet concentration while maintaining a reproducible and pharmaceutically suitable environment for subsequent processing and administration and would provide suitable osmotic conditions for maintaining platelet integrity and function during preparation and subsequent administration.
With regards to claim 16, Andia et al. teaches activating the PRP by adding an activator, including calcium chloride and/or thrombin [Fig. 2].
For claim 17, Meury et al. teaches the use of sonication to mix the activator, e.g. calcium chloride, at a frequency of 25 kHz for 15 seconds causing platelets to release mediators and cytokines [¶ 0014].
It would have been a prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Andia et al. and Shiga et al. with Meury et al. where sonication is taught following adding the activator to the PRP thereby promoting PRP activation resulting in release of platelet-derived mediators and cytokines. Furthermore, a person of ordinary skill would have had a reasonable expectation of success that combining the teachings of Andia et al. and Shiga et al. with the additional teachings of Meury et al. would have resulted in a PRP that is more thoroughly activated with the addition of sonication and would have represented a known PRP-processing technique to the closely related PRP preparation of Andia et al. and Shiga et al. for its established purpose.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Argument
Applicant argues that the Office must determine what is “analogous prior art”. The examiner agrees with this assertion. The cited references are directed to the same field of endeavor as the claimed invention, namely platelet rich plasma processing, activation, preservation, and therapeutic formulation. Andia et al. expressly teaches PRP and PPP fractionation, platelet concentration by centrifugation, resuspension or platelet pellets in PPP, i.e. high purity, platelet activation using either calcium chloride/thrombin or sonication, and lyophilized PRP formulations. Andia et al. also specifically discloses the use of activators prior to lyophilization. Shiga et al. teaches freeze-dried PRP compositions that retain activation capability and growth factor expression after preservation, while Godoi et al. teaches activated PRP gel matrices for sustained biological effect. Each reference is reasonably pertinent to the problem being addressed by Applicant, i.e. preparation of stabilized platelet compositions hiving retained growth factor activity.
Additionally, Applicant’s arguments and supplementary data have been fully considered but are not persuasive. Applicant sates that the submitted experimental results demonstrate that, following freeze drying, PRP containing calcium chloride can be re-dissolved without gel formation or coagulation. However, the presently rejected claims do not require that the freeze-dried composition be capable of re-dissolution without gel formation or coagulation. The claims also do not require any particular reconstitution behavior. Because of this, the asserted results are not commensurate in scope with the presently claimed subject matter and do not distinguish the claimed invention from the cited prior art.
Applicant further argues that Andia et al. resuspended platelet pellets in a predetermined volume of PPP for the purpose of adjusting platelet concentration, whereas Applicant states the recited processing steps for a different purpose. This argument is not persuasive. The claims do not require that mixing the PRP and PPP be performed for Applicant’s stated purpose. Furthermore, Andia et al. is relied upon for teaching the claimed physical operation of combining a platelet concentration with a determined amount of PPP in addition to Andia et al.’s general teachings of PRP concentration, activation, and freeze-drying. The fact that Andia et al. identifies adjustments of platelet concentration as the purpose for combining the platelet preparation with PPP does not negate what it teaches regarding the claimed operation.
Applicant also argues that a skilled artisan would not have readily conceived of first separating PRP and PPP, activating the PRP, centrifuging the activated PRP to remove supernatant, subsequently mixing the activated PRP with PPP, and freeze-drying the resulting composition. However, the rejection is based upon the combined teachings of the cite prior references rather than Andia et al. alone. Andia et al. provides the overall PRP processing framework which includes separation and concentration of PRP, use of PPP with the platelet concentrate, activation, and freeze-drying, while Escobar et al. expressly teaches calcium activation of PRP followed by centrifugation and separation of the resulting supernatant. The claimed process represents a combination and order of known PRP-processing operations used for their established functions. Because of this, the combined teachings of the cited prior art references provide a reasonable expectation of success in arriving at the claimed process.
Lastly, Applicant’s argument for unquantified PRP containing calcium chloride is not persuasive because the claimed preparation is directed towards quantified and activated PRP. The scope of the claims have nothing to do with unquantified PRP. Moreover, the claims do not require that the resulting freeze-dried composition be capable of re-dissolution without gel formation or coagulation. Because of this, claims 1-10, 13-14, and 16-17 are newly rejected under §103.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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