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 .
DETAILED ACTION
This action is response to papers filed January 3, 2024. Claim 23 is an independent claim. Claims 13, 15-17, 21, and 23-37 are under examination to which the following grounds of rejection are applicable.
Priority
The present application is a continuation of Patent No. 18/056, 220 filed November 16 2022 (now US Patent PAT 11752468) , which is a continuation of Patent 16/865, 215 filed May 1, 2020 (now US Patent PAT 11529587). App. ‘220 claims priority to Provisional Applications 63/296,122 filed on November 15, 2019 and Provisional Application 62/843,061 filed on May 3 2019.
Therefore, the earliest priority date for the instant application is May 3, 2019.
Claim Objections
In claim 21, the acronyms “HLA” and “HNA” are recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim.
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 13, 15-17, 21, and 23-37 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.
Claims 13, 15-17, 21, and 23-37 are vague and indefinite because they all recite the phrase "platelet derivative composition" and the metes and bounds of how a composition of platelet can be "a derivative" and still meet the intended limitation of the claim are not clear. It is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization. As such the metes and bounds of the claims are indefinite. It would be remedial to amend the claim language to use the term “a platelet composition obtained from”, which implies a more direct method of acquiring an ETR-binding polypeptide.
Claim 23 is further indefinite in the recitation of the phrase “such as” in line 4 because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 23 recites the term “and/or” in line 9. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only proteins, or all of the proteins and lipids, or, “or” would imply that the proteins and lipids are in the alternative. Appropriate correction is requested.
Claim 23, it is indefinite in its recitation of the phrase “wherein the platelet derivatives have a CD42 percent positivity of at least 75% and a CD41 positivity of at least 55% when measured using flow cytometry, wherein the platelet derivatives have less than 0.5% crosslinking of platelet membranes via proteins and/or lipids present on the membrane.” It is unclear if the percent positivity and the percentage of crosslinking of platelet membranes is directed to the platelet derivatives before rehydration. Moreover, it is unclear what constitutes “crosslinking” and how it is measured.
Regarding claim 23, it is indefinite in its recitation of the term “the membranes” and “platelet membranes” in line 9 as they lacks proper antecedent basis. Claim 23 is drawn to platelet derivatives and not platelets.
Regarding claim 16, it is indefinite in its recitation of the term “the cell membrane” as it lacks proper antecedent basis. Claim 23 recites a “platelet membrane”.
Claims 13, 15, 17, 21, and 24-37 are rendered indefinite insofar as they depend on claim 23.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 13, 15-17, 21, 23-37 are rejected under 35 U.S.C. 103 as being unpatentable over Fitzpatrick et al, (Published: 2011. Cited in IDS filed September 12, 2025. Blood, vol. 118, no. 21, 18 Nov. 2011, pp. 719–719.), in view of Dee et al. (Published: 2010. International Society of Blood Transfusion Vox Sanguinis, Volume 99, Suppl. 1, P-0453, 2010, page 262, Abstract. Cited in IDS filed September 9 2025) and in further view of Zhou et al (Published: 2007. CryoLetters 28(3), 187-196 (2007). Cited in IDS: September 12, 2025) and Lizarbe et al. (Published: 2013. Int J Mol Sci. 2013 Jan 28;14(2):2652-83).
The applied Fitzpatrick et al. reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Fitzpatrick is November 18, 2011. The earliest effective filing date of the instant application is May 3, 2019.
Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 23, Fitzpatrick teaches a method for treating a subject with thrombocytopenia and administering to the subject (page 2 para 2, “In vivo efficacy was evaluated in a ‘Thrombocytopenic rabbit ear bleed model’ and a ‘NHP hemorrhagic shock model’.), comprising rehydrating a platelet derivative composition (page 1 para 2, “LPDH were manufactured by lyophilization using human in date stored platelets (hIDSP) as a source material and a proprietary process developed by Cellphire Inc. Upon product rehydration, increased number of microparticles”), wherein the platelet derivatives have a CD42 percent positivity, and that platelet derivatives express Annexin V (page 1 para 2, “Rehydrated LPDH exhibited an increase in Annexin V binding (85.5±10.9 VS 3.8±1.4 % in fresh platelets) in conjunction with a decrease in GPlb expression (from 97.99±2.36 to 44.36±21.7%).”), wherein the platelet derivative comprises less than 5% microparticles and have microparticles within the size range of 0.5 µm to 5 µm (page 1 para 2, “Upon product rehydration, increased number of microparticles (size <1.03 μm; 35.1 ± 7.5 VS 14.6± 6.6%) and macroparticles (>5.04 μm; 0.74± 1.2 VS 0.02± 0.0)”). Moreover, Fitzpatrick teaches a concentration of particles administered (page 2 para 2, “…resulting in clot strength -85% to that generated by 200,000/μl of hlDSP. LPDH retained the innate ability to adhere to glass-immobilized collagen under high shear similar to freshly isolated platelets”). Additionally, Fitzpatrick teaches that rehydrated platelets had a shorter lag time in thrombin generation, and reduced thrombin-induced aggregation (pp. 1-2, “However, LPDH suspensions in buffer demonstrated preserved responses of thrombin-induced aggregation (78±10 VS 95±1.5% in platelets). In plasma LPDH produced thrombin in a concentration dependent manner as indicated by the rate and extent of total thrombin generation by concentrations between 50,000-500,000 particles/μl. Notably the "lag time" of thrombin generation was also significantly shortened.”). Note: Annexin V binding was 3.8±1.4 % prior to rehydration.
However, Fitzgerald does not explicitly teach that the platelet derivatives are at a concentration of 70,000 particles/µl produce an occlusion time of less than 14 minutes in a thrombin-formation analysis assay, or that the platelet derivatives comprise less than 5% microparticles.
It would have been obvious to one of ordinary skill in the art to optimize processing conditions or utilize separation techniques (e.g. centrifugation or filtration) to reduce the microparticle content to a desired level, including less than 5%, as well as obtain a platelet derivative concentration of 70,000 particles/µl, as it would be routine in the art to do so. Furthermore, the prior art displays that rehydration causes an increase in microparticle population, therefore the percentage of microparticles in a sample would have been a result-effective variable dependent on known parameters and rehydration conditions.
Moreover, although the Fitzgerald only recites that LDPH suspensions preserved thrombin-induced aggregation within the range of 50,000 particles/µL to 500,000 particles/µL, T-TAS occlusion time is a direct and predicable function of the platelet particle concentration, such that when at the claimed concentration, necessarily result in the occlusion time of under 14 minutes. Therefore, the claimed functional limitation is inherent in the prior art.
However, Fitzgerald does not explicitly teach that the CD42 positivity is above 75%, that the platelet derivatives have a CD41 positivity of 55%.
Dee et al. discusses rehydrated platelet derived hemostatic agents that can be reconstituted in water and reduce blood loss in a thrombocytopenic subject. Moreover, Dee teaches that the rehydrated platelets have a select particle size, and demonstrate positive for CD42 (GPIb) and CD41 (GPIIbIIIa), and Annexin V (col 1, “Cellphire has selected particle size distribution, the percentage of particles positive for GPIb, GPIIbIIIa, and Annexin V binding as demonstrative of manufacturing consistency and state of activation”). Moreover, Dee teaches that GPIIb/IIIa and Annexin V expression indicates that samples are platelet derived (col 1, “Samples laveled with GPIIb/GPIIIa-FITC and Annexin V-PE, particles exhibiting fluorescence in excess of isotype are considered platelet/Thrombosome derived”).
It would have been obvious to further include CD41 as an additional platelet derivation marker and ensure consistency in manufacturing and product quality. The analysis of both CD42 and CD41 as taught by the combined teachings of Dee and Fitzpatrick would allow for confirmation of platelet identity, batch consistency and state of activation. Moreover, it would have been obvious to optimize the CD42 and CD41 positivity percentage as these markers are routinely used to assess platelet identity and derivation. Accordingly, selecting a population of platelet derivatives to have a CD42 positivity percentage of at least 75% and 55% of CD41 positivity represents an optimization of a result-effective variable reflecting platelet derivation purity and functionality.
It would have been obvious to optimize aspects of the CD42 and CD41 expression and concentration of particles of the rehydrated platelet derivatives based on influential considerations in the design of the claimed methodology, such as processing conditions (e.g. lyophilization, shear, storage conditions), platelet fragmentation, gating strategy in flow cytometry, and overall purity of starting material, to achieve the desired positivity percentages of CD42 and CD41.
The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[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). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP § 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount.
However, the combined teachings of Fitzgerald or Dee fail to teach that Annexin V has a role in crosslinking of platelet membranes.
Lizarbe teaches that Annexin V has the ability to bind to phosphatidylserine (PS) through a calcium-mediated interaction to form a two-dimensional crystal lattice, and that lattice formation is dependent on the presence of PS on the membrane (crosslinking; see pp. 2885, 4.1.2. Annexins as Membrane Scaffolds, “It is well known that annexins are not only able to interact with membranes and cytoskeleton, but also to form lateral assemblies leading to the formation of two-dimensional crystal structures on the bilayers. In this regard, annexin A5 has the ability to bind in a calcium-dependent manner to PS membranes and to form a two-dimensional crystal lattice through the lateral interaction of protein trimers. It has been proposed that these structures may be involved in stabilizing certain plasma-membrane structures and in changing membrane curvature and cell shape”).
It would have been obvious to one with ordinary skill in the art to expect that the platelet membrane surfaces would support Annexin-mediated assembly and lattice formation (crosslinking) via lateral interaction of protein trimers such that the extent of such membrane-associated protein/lipid networking could be controlled as a result-effective variable.
However, neither Fitzgerald, Dee or Lizarbe do not teach that less than 0.5% of crosslinking of platelet membranes via proteins or lipids is present on the membranes.
Zhou teaches that phosphatidylserine (PS), is normally confined to the inner leaflet of platelet membranes and becomes externalized once activated, which reveals that platelet activation is necessary for platelet coagulation of platelets (pp. 189 para 6, “One of the markers for platelet activation is phosphatidylserine (PS), a negatively charged phospholipid, which is normally confined to the inner leaflet of the platelet membrane. When platelets are activated, PS molecules externalize to the outer leaflet of lipid membrane to provide a membrane surface for the assembly of coagulation factors. Annexin V, a protein that binds PS in the presence of Ca2 +, is widely used to detect PS externalization in activated platelets”). Moreover, Zhou teaches that Annexin V binds externally to PS and used as a marker for platelet activation. Additionally, Zhou establishes that platelet activation, caused by Annexin V binding is unfavorable as “avoiding platelet activation is in order to preserve platelets” (pp. 189 para 5).
A person with ordinary skill in the art would have understood that reducing platelet activation, as taught by Zhou, is desirable to preserve platelet functionality and premature coagulant activity in freeze-dried platelets (before rehydration). Accordingly, a person with ordinary skill in the art would have understood that reducing platelet activation to less than 0.5% would necessarily reduce PS externalization, thereby limiting Annexin V binding, which reduces the extent of Annexin V mediated crosslinking and lattice formation. Since lattice formation is the mechanism in which membrane crosslinking occurs, a reduction in PS exposure would inherently result in a reduction of membrane crosslinking, and avoiding platelets from experiencing premature coagulation prior to administering to the patient. Therefore, the degree of membrane crosslinking is influenced and controlled by the level of platelet activation. Moreover, the percentage of crosslinking platelet membranes is a result-effective variable that a skilled artisan would routinely optimize. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Regarding claim 13, the combined teachings of Fitzgerald, Dee, Lizarbe and Zhou render obvious the claimed methodology. Moreover, Fitzgerald teaches annexin V percent positivity of at least 70% (page 1 para 2, “Rehydrated LPDH exhibited an increase in Annexin V binding (85.5±10.9 VS 3.8±1.4 % in fresh platelets)”).
Regarding claim 24, 25, 31 and 32, the combined teachings of Fitzgerald, Dee, Lizarbe and Zhou render obvious the claimed methodology. Moreover, Fitzgerald teaches the platelet derivatives to have a CD42 percent positivity of at least 79% (page 1 para 2, “Rehydrated LPDH exhibited an increase in Annexin V binding (85.5±10.9 VS 3.8±1.4 % in fresh platelets) in conjunction with a decrease in GPlb expression (from 97.99±2.36 to 44.36±21.7%).”).Moreover, Dee teaches the platelet derivatives to have a CD41 percent positivity of at least 75% (col 1, “Samples laveled with GPIIb/GPIIIa-FITC and Annexin V-PE, particles exhibiting fluorescence in excess of isotype are considered platelet/Thrombosome derived”).
It would have been obvious to optimize aspects of the CD41 and CD42 expression and concentration of particles of the rehydrated platelet derivatives based on influential considerations in the design of the claimed methodology, such as processing conditions (e.g. lyophilization, shear, storage conditions), platelet fragmentation, gating strategy in flow cytometry, and overall purity of starting material, to achieve the desired 75% positivity percentage of CD41, and a positivity percentage of 79% for CD42.
Regarding claim 26 , 27, and 32 the combined teachings of Fitzgerald, Dee, Lizarbe and Zhou render obvious the claimed methodology of claims 16, 23. Moreover, Fitzgerald teaches the platelet derivatives to comprise 2-3.5% of microparticles (page 1 para 2, “Upon product rehydration, increased number of microparticles (size <1.03 μm; 35.1 ± 7.5 VS 14.6± 6.6%) and macroparticles (>5.04 μm; 0.74± 1.2 VS 0.02± 0.0)”) rendering obvious the limitation of less than 3.5% microparticles in claim 32.
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Regarding claim 28 and 29, the combined teachings of Fitzgerald, Dee, Lizarbe and Zhou render obvious the claimed methodology of claims 23, 27. Moreover, Zhou teaches the effect of different saccharides, such as trehalose, and their effect on platelet recovery and activation (page 187, Abstract, “In this study, effects of concentration and type of saccharides, freezing rate and initial cell concentration on the recovery of freeze-dried platelets were investigated… The numerical recovery of freeze-dried platelets was reached as high as (93.0±5.2) % and the recovery of nonactived platelets was reached up to (85.7±3.4) % in the presence of 1 %BSA and 20% trehalose.”). Moreover, Zhou teaches that increased concentration of trehalose resulted in an increased recovery of platelets, and that trehalose had the highest protect efficiency (page 191, para 2, “The highest numerical recovery of freeze-dried platelets was reached (93.0 ± 5.2) % and the highest recovery of non-activated platelets was reached 85.7 ± 3.4% at 20% (w/v) trehalose. For various saccharides with same concentration of 20%, the protective efficiency of each saccharide was as follows: trehalose >maltose > glucose > lactose > sucrose.”; Table 1). Note: Upon calculations made by the Examiner, 1% BSA + 10% trehalose is equivalent to roughly 292mM, absent to any evidence to the contrary.
A person with ordinary skill in the art would have been motivated to utilize trehalose as a protectant for platelet derivatives as it is found to influence the overall recovery of platelet viability after freeze-drying and rehydration. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Regarding claim 33, the combined teachings of Fitzgerald, Dee, Lizarbe and Zhou render obvious the claimed methodology of claim 23. Moreover, Fitzpatrick and Dee teaches the a therapeutically effective amount (Fitzpatrick, page 2 para 2, “…resulting in clot strength -85% to that generated by 200,000/μl of hlDSP. LPDH retained the innate ability to adhere to glass-immobilized collagen under high shear similar to freshly isolated platelets”; Dee, page 262 col 2, “Anesthetized animals were infused with about 2 · 109 In-111-labeled Thrombosomes, fresh rabbit platelets or rabbit FDP over a1 min period. Serial arterial blood samples (100 ll) were obtained over 4 or 24 h.”).
It would have been obvious to one of ordinary skill in the art to optimize processing conditions or utilize separation techniques (e.g. centrifugation or filtration) to obtain a platelet derivative concentration of 70,000 particles/µl, as it would be routine in the art to do so.
Regarding claim 34, the combined teachings of Fitzgerald, Dee, Lizarbe and Zhou render obvious the claimed methodology. Moreover, Zhou teaches that the platelet derivative composition comprises less than or equal to 15% plasma protein (Table 1).
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Regarding claim 35, the combined teachings of Fitzgerald, Dee, Lizarbe and Zhou render obvious the claimed methodology. Moreover, Zhou teaches that the residual moisture content is less than 5% (page 189. Para 2, “The residual water content was the ratio of the lost residual water weight to the initial sample weight. It was typically 0.02 ± 0.01 gig dry mass in our experiments.”).
It would have been obvious to one of ordinary skill in the art to optimize processing conditions or utilize separation techniques (e.g. centrifugation or filtration) to reduce the microparticle content to a desired level, including less than 2-3.5%, as it would be routine in the art to do so. Furthermore, the prior art displays that rehydration causes an increase in microparticle population, therefore the percentage of microparticles in a sample would have been a result-effective variable dependent on known parameters and rehydration conditions.
Regarding 36-37, wherein the platelet derivative composition is prepared by the process comprising, performing tangential flow filtration (TFF) of a platelet composition comprising platelets in a preparation agent comprising a buffering agent, trehalose in an amount in the range of 10 mM to 500 mM, and polysucrose in an amount in the range of 3% to 7%, thereby preparing a TFF-treated composition comprising at least 1000 x 103 platelets/ l in an aqueous medium having less than or equal to 7.5% plasma protein; and freeze drying the TFF-treated composition comprising platelets in the aqueous medium to form the platelet derivative composition holds no patentable weight as it is a product-by-process claim.
It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). It is noted that, if the prior art discloses identical chemical structure, the properties applicant discloses and/or claims are necessarily present, In re Spada, 911 F.2d 705, 709, 15 USPQ2d.
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Claim(s) 15, 16 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Fitzpatrick et al, (Published: 2011. Cited in IDS filed September 12, 2025. Blood, vol. 118, no. 21, 18 Nov. 2011, pp. 719–719.), in view of Dee et al. (Published: 2010. International Society of Blood Transfusion Vox Sanguinis, Volume 99, Suppl. 1, P-0453, 2010, page 262, Abstract. Cited in IDS filed September 9 2025) and in further view of Zhou et al (Published: 2007. CryoLetters 28(3), 187-196 (2007). Cited in IDS: September 12, 2025) and Lizarbe et al. (Published: 2013. Int J Mol Sci. 2013 Jan 28;14(2):2652-83) and in further view of Hou et al. (Published: 2015. J Biomed Res. 2015 Oct 30;29(6):437–44.)
With regard to claim 23, the combined teachings of Fitzpatrick, Dee, Zhou, and Lizarbe render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 23.
However, the combined teachings fail to teach that the platelet derivatives have a CD62 percent positivity of at least 80%, and fibrinogen associated in the cell membrane.
Regarding claims 15 and 16, Hou teaches that platelet activation is induced by collagen and ligands of adhesion receptors, such as P-selectin (CD62) and fibrinogen (pp. 439, col 1, “Platelet activation exposes PS on the membrane surface that drives the cell-based thrombin generation and facilitates further platelet activation. Activation signals induced by thrombin, collagen, or ligands of adhesion receptors with the addition of shear stress, can lead to platelet granule release. Platelet adhesion molecules, P-selectin, integrins, VWF, fibrinogen, fibronectin, vitronectin, multimerin, platelet factor 4, and approximately 300 other proteins are contained within the α-granules”).
It would have been obvious for someone with ordinary skill in the art to use markers for fibrinogen and CD62 to characterize platelet activation and drive thrombin-generation in the platelet derivatives taught by the combined teachings of Fitzpatrick, Dee, Zhou and Lizarbe, as platelet derivatives are prepared directly from platelets. Therefore, a skilled artisan would reasonably expect that platelet-derived compositions would maintain expression of CD62 and fibrinogen, as they are known activation markers in platelets.
However, Hou does not explicitly teach that platelet derivatives have a CD62 percent positivity of 80%.
It would have been obvious to optimize aspects of the CD62 expression and concentration of particles of the platelet derivatives based on influential considerations in the design of the claimed methodology, such as processing conditions (e.g. lyophilization, shear, storage conditions), platelet fragmentation, gating strategy in flow cytometry, and overall purity of starting material, to achieve the desired positivity percentages of CD62.
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Claim(s) 17 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Fitzpatrick et al, (Published: 2011. Cited in IDS filed September 12, 2025. Blood, vol. 118, no. 21, 18 Nov. 2011, pp. 719–719.), in view of Dee et al. (Published: 2010. International Society of Blood Transfusion Vox Sanguinis, Volume 99, Suppl. 1, P-0453, 2010, page 262, Abstract. Cited in IDS filed September 9 2025) and in further view of Zhou et al (Published: 2007. CryoLetters 28(3), 187-196 (2007). Cited in IDS: September 12, 2025) and Lizarbe et al. and Dielis et al. (Published: 2008. J Thromb Haemost. 2008 Jan;6(1):125-31.).
With regard to claim 23, the combined teachings of Fitzpatrick, Dee, Zhou, and Lizarbe render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 23.
However, Fitzpatrick does not explicitly teach that at a concentration of 4,800 particles/µL causes a generation of thrombin peak height (TPH) of at least 25mM. Moreover, Fitzpatrick teaches thrombin generation at a specific concentration (pp. 1-2, “In plasma LPDH produced thrombin in a concentration dependent manner as indicated by the rate and extent of total thrombin generation by concentrations between 50,000-500,000 particles/μL. Notably the "lag time" of thrombin generation was also significantly shortened.).
Dielis teaches that thrombin generation depends on multiple coagulation factors and inhibitors (pp. 125, col 1, The lag time, ETP and peak height of thrombin generation depend on the levels of multiple coagulation factors and inhibitors)
It would have been obvious to one of ordinary skill in the art to optimize processing conditions or utilize separation techniques (e.g. centrifugation or filtration) to obtain a platelet derivative concentration of 4800 particles/µl in order to achieve a certain TPH, as it would be routine in the art to do so. Modifying the specific concentration of particles would reasonably result in improved thrombin generation and coagulation performance.
Moreover, although the references do no expressly disclose a peak thrombin height of 25mM, Peak thrombin generation is a direct and predictable function of coagulating particle concentration. As a result, when the concentration of platelets taught by both Dielis and Fitzpatrick is at the desired concentration, tit necessarily produces the thrombin generation curves with peak heights of 25mM. Therefore, the recited peak thrombin height is an inherent property of the platelet-derived composition.
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Claim(s) 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Fitzpatrick et al, (Published: 2011. Cited in IDS filed September 12, 2025. Blood, vol. 118, no. 21, 18 Nov. 2011, pp. 719–719.), in view of Dee et al. (Published: 2010. International Society of Blood Transfusion Vox Sanguinis, Volume 99, Suppl. 1, P-0453, 2010, page 262, Abstract. Cited in IDS filed September 9 2025) and in further view of Zhou et al (Published: 2007. CryoLetters 28(3), 187-196 (2007). Cited in IDS: September 12, 2025) and Lizarbe et al. (Published: 2013. Int J Mol Sci. 2013 Jan 28;14(2):2652-83) and UCLA Division of Transfusion Medicine (Published: 2016. HLA Antibody Educational Material).
With regard to claim 23, the combined teachings of Fitzpatrick, Dee, Zhou, and Lizarbe render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 23.
However, the combined teachings do not disclose the use of platelet derivates that are negative for an HLA Class I or Class II.
UCLA teaches that the presence of HLA is dangerous for blood transfusion (paragraph 2, “However, HLA antibodies in donated plasma or plasma blood products may be dangerous to transfusion recipients.”).
It would have been obvious to explicitly use negative-HLA Class I or Class II antibodies to reduce blood-transfusion risk as platelets are a derivative from blood, therefore, selecting an antibody-negative composition would be an obvious safety implementation for downstream usage. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
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Claim(s) 23 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Fitzpatrick et al, (Published: 2011. Cited in IDS filed September 12, 2025. Blood, vol. 118, no. 21, 18 Nov. 2011, pp. 719–719.), in view of Dee et al. (Published: 2010. International Society of Blood Transfusion Vox Sanguinis, Volume 99, Suppl. 1, P-0453, 2010, page 262, Abstract. Cited in IDS filed September 9 2025) and in further view of Zhou et al (Published: 2007. CryoLetters 28(3), 187-196 (2007). Cited in IDS: September 12, 2025) and Lizarbe et al. (Published: 2013. Int J Mol Sci. 2013 Jan 28;14(2):2652-83) and Fitzpatrick et al. (Hereafter disclosed as “Fitzpatrick 2”. Published: 2013. Transfusion. 2013 Jan;53 Suppl 1:100S-106S. Cited in IDS: 9/12/2013).
With regard to claim 23, the combined teachings of Fitzpatrick, Dee, Zhou, and Lizarbe render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 23.
However, the combined teachings do not explicitly disclose the use of polysucrose in a concentration range of 3% to 10% (w/v).
Fitzpatrick 2 discloses a platelet derived hemostatic agent that utilizes polysucrose and sucrose for stabilization (Abstract, “We report on an infusible lyophilized platelet-derived hemostatic agent stabilized with trehalose and polysucrose prior to and during lyophilization”)
A person with ordinary skill in the art would have recognized that trehalose used in combination with another saccharide, polysucrose, as taught by Fitzpatrick 2, ensures stabilization of the platelet-derived compositions and utilize it in the invention taught by Fitzpatrick. Moreover, it would have been obvious to optimize aspects of the rehydrated platelet derivatives, specifically the concentration of polysucrose, based on influential considerations in the design of the claimed methodology, such as processing conditions (e.g. lyophilization, shear, storage conditions), platelet fragmentation, number of particles, and concentration of polysucrose, to achieve the desired concentration of 3%-10% (w/v).
The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature is critical. “[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). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
MPEP § 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13, 15-17, 21, and 23-37 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-25 of US Patent 11,752,468 and claims 1-29 of US Patent 11,529,587. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the cited claims of US Patent 11,752,468 and US Patent 11,529,587.
Claim 1 of US Patent 11,752,468 is directed to:
“A process for preparing a thermally-treated platelet composition, the process comprising: performing tangential flow filtration (TFF) of a platelet composition comprising platelets in a preparation agent comprising a buffering agent, between 10 mM and 1000 mM of saccharides comprising a monosaccharide and/or a disaccharide, and polysucrose in an amount in the range of 3% to 7%, wherein the TFF is performed until a particular residual plasma protein endpoint is reached, thereby preparing a TFF-treated composition comprising at least 1000×10^3 platelets/μl in an aqueous medium having less than or equal to 15% plasma protein and having less than 5.0% microparticles by scattering intensity; freeze drying the TFF-treated composition comprising platelets in the aqueous medium to form a freeze-dried platelet composition; and heating the freeze-dried platelet composition at a temperature in the range of 60° C. to 85° C. for at least 1 hour to not more than 36 hours to thermally treat the freeze-dried platelets in the freeze-dried platelet composition to form the thermally-treated platelet composition, wherein the thermally-treated platelets in the thermally-treated platelet composition are capable of generating thrombin in an in vitro thrombin formation assay.”
Moreover, claim 2 of Patent ‘468 recites, “wherein at least 79% of the thermally-treated platelets in the thermally-treated platelet composition are CD42 positive, which encompasses claim 24 of the instant application.
Claim 6 and 7 of Patent ‘468 are drawn to specific percentage ranges of CD42 and CD41, which encompass claims 24, 25, and 31 of the instant application.
Claim 8 of Patent ‘468 is directed to specific saccharides used in the process of claim 1 which encompasses claim 28 and 29 of the instant application.
Claim 10 of Patent ‘468 recites “The process of claim 10, wherein the disaccharide is trehalose in an amount in the range of 50 mM to 500 mM.”, which encompasses claim 29 of the instant application.
Claim 13 of Patent ‘468 recites “The process of claim 12, wherein the thermally-treated platelets in the thermally-treated platelet composition when at a concentration of at least about 70×10.sup.3 particles/μL, produce an occlusion time of less than 14 minutes in a total thrombus-formation analysis system (T-TAS) assay”, which encompasses claim 17 of the instant application.
Claim 20 of Patent ‘468 recites “The process of claim 15, wherein the thermally-treated platelets in the thermally-treated platelet composition: a) when at a concentration of about 4.8×10.sup.3 particles/μL generate a thrombin peak height (TPH) of at least 25 nM when in the presence of a reagent containing tissue factor and phospholipids; and b) when at a concentration of at least about 70×10.sup.3 particles/μL, produce an occlusion time of less than 14 minutes in a total thrombus-formation analysis system (T-TAS) assay.”, which encompass claims 17 and 23.
As described above, the conflicting patent and the instant application significantly overlap. Moreover, conflicting patent ‘468 teaches the limitations of the instant application. Although the Patent ‘468 teaches a preparation agent in the range of 10mM to 1000mM and heating the freeze-dried platelets within a range of 60°F-85°F, a skilled artisan would have been motivated to optimize aspects of the filtration design and preparation of the platelet derivative composition to arrive at the instant invention. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been obvious for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. Moreover, the claims define substantially the same invention as the instant claims, merely presented in a different format.
Claim 1 of US Patent 11,529,587 recites:
“A process for preparing a thermally-treated platelet composition, the process comprising: performing tangential flow filtration (TFF) of a platelet composition with a preparation agent comprising a buffering agent, trehalose in an amount in the range of 10 mM to 500 mM, and polysucrose in an amount in the range of 3% to 7%, thereby preparing a TFF-treated composition comprising at least 1000×10.sup.3 platelets/μl in an aqueous medium having less than or equal to 7.5% plasma protein and having less than 5.0% microparticles by scattering intensity, freeze drying the TFF-treated composition comprising platelets in the aqueous medium to form a freeze-dried platelet composition; and heating the freeze-dried platelet composition at a temperature in the range of 60° C. to 85° C. for at least 1 hour to not more than 36 hours to thermally treat the freeze-dried platelets in the freeze-dried platelet composition to form the thermally-treated platelet composition, wherein thermally-treated platelets in the thermally-treated platelet composition have a potency of at least 1.5 thrombin generation potency units (TGPU) per 10.sup.6 thermally-treated platelets.”
Moreover, Claim 13 and 24 of Patent ‘587 discuss that the platelets need to be negative for HLA Class I and Class II, and negative for HNA Antibodies test, which encompasses claim 21 of the instant application.
Claim 5 of Patent ‘587 recites “wherein at least 55% of the thermally-treated platelets in the thermally-treated platelet composition are CD41 positive”, which encompasses claim 23 and 25 of the instant application.
Claim 6 of Patent ‘587 recites, “wherein at least 70% of the thermally-treated platelets in the thermally-treated platelet composition are annexin V positive”, which encompasses claim 13 of the instant application.
Claim 8 of Patent ‘587 recites, “ wherein at least 80% of the thermally-treated platelets in the thermally-treated platelet composition are CD62 positive”, which encompasses claim 15 of the instant application.
Claim 9 of Patent ‘587 recites “wherein at least some of the thermally-treated platelets in the thermally-treated platelet composition have fibrinogen associated with their cell membrane.”, which encompasses claim 16 of the instant application.
Claim 18 of Patent ‘587 recites “ wherein trehalose in the preparation agent is in an amount in the range of 50 mM to 500 mM and the polysucrose is in an amount in the range of 3% to 6%.”, which encompass claims 29 and 30 of the instant application.
Claim 20 of Patent ‘587 recites “wherein the polysucrose in the preparation agent is in an amount in the range of 3% to 6%.”, which encompasses claim 30 of the instant application.
Claim 29 of Patent ‘587 recites “wherein at least 80% of the thermally-treated platelets in the thermally-treated platelet composition are CD42 positive”, which encompasses claim 24 of the instant application.
Claim 23 of the instant invention is directed to a method for treating thrombocytopenia, involving rehydrating a platelet derivative composition and administering it to the subject, wherein the administered platelet derivatives exhibit specific functional characteristics, which include a CD42 percent positivity of at least 75%, CD41 positivity of at least 55%, a microparticle average diameter to be 5µm, and platelet derivatives have less than 0.5% crosslinking of platelet membranes via proteins and/or lipids present on the membranes.
Moreover, Claim 36 and 37 of the instant application are directed to a method of preparing a platelet derivative composition by performing tangential flow filtration (TFF).
Both Patents ‘468 and ‘587 have the same platelet compositions recited in the instant application, differing primarily in that the existing patents are drawn to a method of making, whereas the instant claim is drawn to a method of using the platelet derivative composition to treat thrombocytopenia.
It would have been obvious to one of ordinary skill in the art to administer the rehydrated platelet compositions of ‘468 and ‘587 patents to a subject suffering from thrombocytopenia, as the patents are expressly designed to aid in platelet function (e.g. thrombin peak height, thrombin generation), which addresses the issues with clotting and low platelet count found in thrombocytopenia. The use of a composition for its intended purpose represents a routine and expected use of the composition, therefore not rendering it patentable distinct.
The US Patent 11,752,468 and US Patent 11,529,587 claim methods for preparing a thermally-treated platelet composition, but double-patenting rejections of claims to a method of use based on a claimed method for preparing a thermally-treated platelet composition are proper. This rejection is necessitated by the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc. v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates the preclusion of double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Conclusion
No claims are allowed.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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