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 .
Formal Matters
Applicant’s response filed January 10, 2023 has been received and entered into the application file. All arguments have been fully considered. Claims 1-6, 8-12, 14-18 and 20-23 are currently pending. Claims 1, 4-6, 8, 10 and 21 are currently amended. Claims 7, 13 and 19 are cancelled. Claims 6, 8-9, 18 and 20 are withdrawn. Claims 22-23 are new.
Claim Objections
Claim 21 is objected to because of the following informalities: abbreviation.
The acronym ACD (Acid-Citrate-Dextrose) should first be spelled out upon its first usage in a claim.
Appropriate correction is required.
Claim Interpretation
Claims 1 and 10 have been amended to recite the phrase “… lyophilized dry platelet lysate material being free of any gelatinizing-inhibiting substance…” It is noted that Applicant’s specification (page 8, lines 14-21 and page 9, lines 11-20) discloses the human platelet lysate is generated by apheresis from plasma supplemented with the anticoagulant Acid-Citrate-Dextrose (gelatinizing-inhibiting substance). Thereafter, the lyophilized platelet lysate is reconstituted without the addition of gelatinization-inhibiting substances such as heparin in order to permit spontaneous gelatinization (coagulation) due to the calcium that is present in the solvent used for reconstitution (specification at page 9, lines 32-33; and page 15, lines 29-31). Therefore, given Applicant’s specification discloses the lyophilized platelet lysate is prepared without the addition of any exogenous gelatinization-inhibiting substances such as heparin, this limitation is interpreted to exclude the addition of exogenous anticoagulants to the lyophilized platelet lysate. In view of Applications specification, this limitation does not exclude the use of anticoagulants for collection or generation of platelets from plasma.
Further regarding claim 1 and the limitation “wherein the lyophilized dry platelet lysate material is configured to be reconstituted by addition of water at a place of use resulting in spontaneous gelatinization without addition of a coagulation-inducing agent”, it is noted the claim does not positively recite an active step of adding water to produce spontaneous gelatinization. This limitation is directed to the intended use of the produced lysate material “at a place of use”, which does not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
Likewise, regarding claims 10 and 21, claim 10 recites the limitation “adding water to the lyophilized dry material at a place of use, wherein the lyophilized dry material spontaneously gelatinizes due to the absence of any gelatinizing-inhibiting substance”, and claim 21 recites the limitation “the three-dimensional substrate for cultivating cells is prepared by adding water to the lyophilized dry material at the place of use.” Thus, this limitation is also directed to the intended use of the product, i.e. “…adding water…..at a place of use…”. This limitation does not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
Claim Rejections - 35 USC § 112
Rejection Withdrawn
RE: Rejection of Claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
Applicant’s amendment submitted January 10, 2023 has amended claim 4 to recite “wherein said lyophilized dry platelet lysate material comprises 1-40% blood platelet lysate.” The amendment provides sufficient clarification regarding the claimed concentration range for the blood platelet lysate. Therefore, the previous rejection is withdrawn.
Claim Rejections - 35 USC § 102
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 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
New Ground of Rejection, Necessitated by Amendment
Claim(s) 1-5, 10-12, 14-15 and 23 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Patel et al., (US 2013/0195959; IDS 1/11/2019) (“Patel”).
Claims 1 and 10 have been amended to remove the limitation directed to the thrombocyte concentrate comprising platelets supplemented with Acid-Citrate-Dextrose (ACD). Claims 1 and 10 now recite “…providing a thrombocyte concentrate comprising platelets…”
The preamble of claims 1 and 10 recites the phrase “for preparing a three-dimensional substrate for cultivating cells” and claim 10 at lines 10-11 further recites the phrase “preparing the three-dimensional substrate for cultivating cells. It is noted these limitations are directed to the intended use of the lyophilized dry platelet lysate material that is produced by the claimed method. The claims do not recite any active steps regarding preparing the three-dimensional substrate and culturing cells.
M.P.E.P. § 2111.02 reads, "If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction." As such, the limitation “substrate for cultivating cells” does not affect the patentability of the claimed method. Methods are defined by their constituent steps, not by an intended use or application.
Further regarding claims 1 and 10 and the limitations directed at the lyophilized platelet material being free of any gelatinizing-inhibiting substance, it is noted, as discussed above at Claim Interpretation, this limitation is interpreted to exclude the addition of exogenous anticoagulants to the lyophilized platelet lysate and does not exclude providing a thrombocyte concentrate that is generated from plasma supplemented with anticoagulants, such as the anticoagulant Acid-Citrate-Dextrose (ACD).
Regarding claims 1 and 10, Patel is directed to a method of preparing a platelet lysate composition for therapeutic use or as a culture medium. The method comprises steps of concentrating platelets from a platelet source, lysing the platelets to form a plurality of lysates, and further lyophilizing the lysates to form lyophilized platelet lysates containing released concentrations of available growth factors, cytokines, and chemokines (paragraph [0002]-[0003]).
Patel’s Example 2 prepares a lyophilized platelet rich plasma lysate using the method of Example 1 (paragraph [0036]) with the additional step of processing the blood using a commercially available PRP preparation device such as the Magellan PRP device, after the blood is collected. The lysing and lyophilization steps are conducted as in Example 1 (paragraph [0037]), specifically by collecting peripheral blood, which reads on “providing a thrombocyte concentrate”. The collected blood is further processed using a commercial PRP preparation device. The platelet rich portion is removed and tubes of the platelet rich portion are placed into a freezing range of -190°C to -80°C for a period of 24 hours. After 24 hours, the platelets are lysed by thawing quickly at 37°C. After thawing, the tubes are then returned for another freeze cycle within the same freezing range for a period of 24 hours. The freeze-thaw is repeated at least once, and more typically, repeated at least twice, e.g., 3 to 6 freeze-thaw cycles, which reads on “lysing said platelets to produce a platelet lysate” (claim 1) and “lysing the blood platelets to produce a platelet lysate” (claim 10). After the last thaw cycle, the tubes are refrozen at -80°C and stored overnight. The following day, the tubes are lyophilized, which reads on “lyophilization of said platelet lysate, so as to provide a lyophilized dry platelet lysate gel material” (claim 1) and “lyophilization of said platelet lysate to provide the lyophilized dry material” (claim 10) . Upon lyophilization the platelet lysate product can be stored at room temperature for at least a year, or if at -80°C, for example, a period of 5 years. It is noted that the steps of lysing and lyophilizing can result in varying concentrations of platelet lysate (e.g., 30%, 50%, 70%, 90%, 100%). Patel’s method disclosed in Example 1 is free of gelatinizing-inhibiting substances. Thus, Patel’s method produces a lyophilized dry platelet lysate material being free of any gelatinizing-inhibiting substance, thus anticipating claims 1 and 10.
Further regarding claims 1 and 10 and the limitations “wherein the lyophilized dry platelet lysate material is configured to be reconstituted by addition of water at a place of use resulting in spontaneous gelatinization without addition of a coagulation-inducing agent” (claim 1) and “preparing the three-dimensional substrate for cultivating cells by adding water to the lyophilized dry material at a place of use, wherein the lyophilized dry material spontaneously gelatinizes due to the absence of any gelatinizing-inhibiting substance” (claim 10), it is noted, as discussed above at Claim Interpretation, the claims do not positively recite an active step of adding water to produce spontaneous gelatinization. This limitation is directed to the intended use of the produced lysate material “at a place of use”, which does not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
It is noted however, that Patel (paragraph [0030]) teaches the dry (lyophilized) platelet lysate material (LPL) is formulated for rehydration (reconstitution by adding water) to be used as a gel. Thus, Patel’s dry platelet lysate material is configured to be reconstituted by the addition of a solvent comprising water (rehydration).
Regarding claims 2-3 and 12, Example 3 of Patel (paragraphs [0038]-[0044]) teaches adding the lyophilized platelet lysate (LPRPL product) to supplement tissue culture media for human cell culture. For example, 10 mL of LPRPL can be used to prepare 97 mL of DMEM (i.e. standardized medium composition), thus anticipating claims 2-3 and 12.
Regarding claim 5, Example 1 teaches the blood platelets are lysed by a freeze-thaw process, thus anticipating claim 5.
Regarding claims 4 and 14-15, as set forth above, Example 1 (paragraphs [0036]) of Patel teaches lysing and lyophilizing steps can result in varying concentrations of platelet lysate (e.g., 30%, 50%, 70%, 90%, 100%), thus anticipating claims 4 and 14-15. MPEP 2131.03
Regarding claim 11 and the limitation “wherein the cells are mesenchymal stromal cells”, it is noted, as discussed above regarding claim 10, the limitation “for cultivating cells” is directed to the intended use of the product produced by the instant method, that is “at a place of use” water will be added to form the three-dimensional substrate for cultivating the cells. Claim 10 does not recite an active step of adding cells. Therefore, the recited mesenchymal stromal cells (MSCs) are also directed to the intended use of the product produced by the claimed method.
As such, claim 11 does not further limit parent claim 10, and is included in the rejection of claim 10.
Regarding claim 23, it is noted that claim 23 depends directly from claim 11, and thus depends indirectly from claim 10. As set forth above at the rejection of claim 10, it is noted that the limitations directed to the cultivation of cells are directed to the intended use of the platelet lysate product produced by the claimed method. Claim 23 recites the limitation “wherein the lyophilization has no effect on a differentiation potential and immunophenotype profile of the MSCs”. For the reasons discussed above regarding claims 10 and 11, this limitation is also directed to the intended use of the product produced by the claimed method.
As such, claim 23 does not further limit claims 10 or 11, and is included in the rejection of claim 11.
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 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.
New ground(s) of Rejection, Necessitated by Amendment
Claims 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Patel as applied to claims 1-5, 10-12, 14-15 and 23 above.
The teaching of Patel is set forth above and anticipates claims 1-5, 10-12, 14-15 and 23.
Regarding claims 16 and 17 and the claimed ranges of blood platelet lysate, it is noted that although Example 1 of Patel (paragraphs [0036]) teaches lysing and lyophilizing steps can result in varying concentrations of platelet lysate (e.g., 30%, 50%, 70%, 90%, 100%). Patel does not further teach platelet lysate concentrations of 1-20% (claim 16), or 5-15% (claim 17). Although Patel does not further teach the claimed ranges, it would have been prima facie obvious to one having ordinary skill in the art at the time of the invention to optimize the concentration of platelet lysate as a matter of routine experimentation as it is a recognized result effective variable, as Patel indicates the lysing and lyophilization steps provide the various concentrations of platelet lysate thus releasing growth factors and cytokines that are useful as cell culture supplements (paragraph [0034]). Moreover, at the time of the claimed invention, one of ordinary skill in the art would have been motivated by routine practice to optimize the concentration with a reasonable expectation for successfully forming a product comprising lysed platelets and the resulting released growth factors and cytokines that are useful as cell culture supplements; thus, meeting the limitation of claims 16 and 17.
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Patel, as applied to claims 1-5, 10-12, 14-15 and 23 above, and further in view of Wagner (previously cited):
The teaching of Patel is set forth above and anticipates claims 1-5, 10-12, 14-15 and 23.
Regarding claims 21 and 22 and the limitations directed to supplementing the thrombocyte (platelet) concentrate with Acid-Citrate-Dextrose (ACD), Patel teaches the use of anticoagulants when concentrating or collecting platelets. However, Patel does not specifically teach the anticoagulant is Acid-Citrate-Dextrose (ACD) as recited in claims 21 and 22.
However, Wagner is directed to a method for cultivating cells (mesenchymal stromal cells or fibroblasts) on/in the surface of a three-dimensional gelled scaffold comprising 1-60% human platelet lysate (HPL) (page 3, lines 8-20). Wagner (page 9, lines 20-25) further teaches processing and concentrating platelets to produce a 200 mL platelet concentrate supplemented with the anticoagulant Acid-Citrate-Dextrose (ACD), prior to lysing the platelets to produce a platelet lysate.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to substitute the well-known plasma anticoagulant Acid-Citrate-Dextrose (ACD), as taught by Wagner, as the plasma anticoagulant in the method of Patel for the predictable result of successfully inhibiting unwanted coagulation of the concentrated thrombocytes (platelets), thus meeting the limitation of claims 21 and 22. Wagner has shown that ACD is a well-known and effective anticoagulant; thus one would have had a reasonable expectation of successfully substituting Acid-Citrate-Dextrose (ACD) in the method of Patel. Substitution of one element (anti-coagulant) for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Further regarding claim 21 and the limitation “the three-dimensional substrate for cultivating cell is prepared by adding water to the lyophilized dry material at the place of use”, it is noted as discussed above at Claim Interpretation regarding claim 10, the limitation directed to preparing the three-dimensional substrate at a place of use is directed to the intended use of the product prepared by the claimed method. That is, at a future time (place of use) the lyophilized platelet lysate will be reconstituted to result in the formation of a gel that provides the three-dimensional substrate for cultivating cells. As such, claim 21 does not further limit claim 10, and is included in the rejection of claim 10.
Rejection(s) Maintained
Claims 1-5, 10-12, 14-17 and 21, and new claims 22-23, are rejected under 35 U.S.C. 103 as being unpatentable over Wagner et al., (WO 2013/000672, previously cited; IDS 1/11/2019) (“Wagner”), in view of Patel et al., (US 2013/0195959; previously cited) (“Patel”).
The rejection has been updated in view of Applicant’s claim amendment submitted January 10, 2023.
Regarding claim 1, Wagner is directed to a method for cultivating cells (mesenchymal stromal cells or fibroblasts) on/in the surface of a three-dimensional gelled scaffold comprising 1-60% human platelet lysate (HPL) (page 3, lines 8-20). Wagner teaches a two-phase system comprising (a) a liquid medium and (b) a three-dimensional, gel-like substrate. The three-dimensional, gel-like substrate comprises blood platelet lysate and is free of a gelatinization-inhibiting substance, e.g. heparin (page 3, lines 13-15; page 15, lines 7-8; FIG. 8A). The liquid medium comprises the blood platelet lysate in combination with a gelatinization-inhibiting substance (page 6, lines 10-13).
Wagner (page 5, lines 12-28, to page 6, lines 1-8) specifically teaches the following method:
a) Providing a thrombocyte concentrate, reads on “providing a thrombocyte concentrate comprising platelets”;
b) Harvesting blood platelets from said concentrate;
c) Lysing said platelets, reads on “lysing the blood platelets so as to produce a platelet lysate”;
d) Adding at least one medium component to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate; and
e) Allowing the blood-platelet-lysate-medium to gelatinize at approximately 37 °C so as to obtain a gel-like substrate (i.e. three-dimensional substrate, see FIG. 1) comprising blood platelet lysate (HPL-gel substrate).
Thus, Wagner’s method reads on “A method for producing a material for preparing a three-dimensional substrate for cultivating cells”.
Wagner teaches the blood platelet lysate, either pure or diluted, spontaneously gelatinizes at approximately 37 °C (page 5, lines 22-25). Wagner specifically teaches the three-dimensional, gel-like substrate comprising the blood platelet lysate is substantially devoid of a gelatinization-inhibiting substance (page 3, lines 13-16; page 6, lines 10-13; and page 15, lines 6-8). Thus, Wagner’s disclosed three-dimensional platelet lysate gel-material reads on, “…being free of any gelatinizing-inhibiting substance…”.
Wagner further teaches the medium component comprises a standardized medium composition for cell culture, e.g. DMEM low glucose (DMEM-LG). Wagner further teaches the culture medium contains essential growth factors and all necessary nutrients for cell cultures without undesired serum components. Furthermore, the substrate may comprise 1 -40 % blood platelet lysate, specifically the gel-like substrate according to the invention may comprise 10 % HPL (human platelet lysate), 89 % DMEM, and 2mM L-glutamine (page 5, lines 26-28 to page 6, lines 1-8).
Further regarding claim 1, it is noted that Wagner does not further teach lyophilization of the platelet lysate prior to addition to the culture medium for preparing the gel-like substrate. However, Patel is directed to a method of preparing a platelet lysate composition for therapeutic use or as a culture medium. The method comprises steps of concentrating platelets from a platelet source, lysing the platelets to form a plurality of lysates, and further lyophilizing the lysates to form lyophilized platelet lysates containing released concentrations of available growth factors, cytokines, and chemokines (paragraph [0002]-[0003]).
Patel (Example 1), as set forth above, teaches well-known methods for lyophilizing platelet lysates, and thereafter rehydrating for immediate use (Example 4), or the product can be stored for extended periods of times at room temperature, or even years at below freezing temperatures, such as storage at about -80°C, for about 5 years or more (Example 1). Thereafter, the lyophilized platelet lysate product is reconstituted for immediate use when needed, specifically using a liquid medium such as DMEM or saline (paragraphs [0027]-[0028] and [0033]). Thus, Patel has established it was well-known in the art to lyophilize platelet lysate products in order to have a readily available off-the-shelf product that is useful as a cell culture supplement that provides beneficial growth factors and cytokines (paragraph [0034]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to lyophilize the platelet lysate of Wagner in order to provide a dry product that can be easily stored at room temperature and thus does not require expensive freezers, as well as being readily available at the time of need, thus permitting the advance preparation of the product.
The person of ordinary skill in the art would have been motivated to modify the method of Wagner to include lyophilizing the platelet lysate, as taught by Patel, for the predictable result of successfully preserving the platelet lysate in a manner that permits cost-cutting storage at room temperature and advance preparation, therefore being readily available at the time of need, thus meeting the limitation of claim 1.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Wagner and Patel because each of these teachings are directed at using platelet lysates in cell culture as well as for therapeutic uses.
Further regarding claims 1 and 10 and the limitations “wherein the lyophilized dry platelet lysate material is configured to be reconstituted by addition of water at a place of use resulting in spontaneous gelatinization without addition of a coagulation-inducing agent” (claim 1) and “preparing the three-dimensional substrate for cultivating cells by adding water to the lyophilized dry material at a place of use, wherein the lyophilized dry material spontaneously gelatinizes due to the absence of any gelatinizing-inhibiting substance” (claim 10), it is noted, as discussed above at Claim Interpretation, the claims do not positively recite an active step of adding water to produce spontaneous gelatinization. This limitation is directed to the intended use of the produced lysate material “at a place of use”, which does not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
Regarding claims 2-4, it is noted Wagner teaches adding at least one standardized medium composition for cell culture, specifically DMEM, to obtain a medium comprising 1-60% blood platelet lysate, thus meeting the limitation of claims 2-4.
Regarding claim 5, as set forth above regarding claim 1, Wagner teaches platelet lysates can be generated by a simple freeze-thaw process (page 1, lines 24-25), thus meeting the limitation of claim 5.
Regarding claims 10 and 21, and the limitations directed to preparing a three-dimensional substrate for culturing cells, it is noted as discussed above at Claim Interpretation, claims 10 and 21 indicate the preparation is “at a place of use” and thus is directed to the intended use of the produced product. These limitations do not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
It is noted however, Wagner teaches adding DMEM to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate; and allowing the blood-platelet-lysate-medium to gelatinize at approximately 37 °C therefore obtaining a gelled substrate (i.e. preparing the three-dimensional substrate) comprising blood platelet lysate. Cells were thereafter seeded on the HPL gel (human platelet lysate gel) (FIG. 1 and page 5, lines 12-28, to page 6, lines 1-8; page 18, lines 25-30; page 19, lines 15-17).
Regarding claim 11 and the limitation “wherein the cells are mesenchymal stromal cells”, it is noted, as discussed above regarding claim 10, the limitation “for cultivating cells” is directed to the intended use of the product produced by the instant method, that is “at a place of use” water will be added to form the three-dimensional substrate for cultivating the cells. Claim 10 does not recite an active step of adding cells. Therefore, the recited mesenchymal stromal cells (MSCs) are also directed to the intended use of the product produced by the claimed method.
As such, claim 11 does not further limit parent claim 10, and is included in the rejection of claim 10.
However, it is noted that Wagner teaches seeding mesenchymal stem cells (MSCs) on the HPL-gel substrates (platelet lysate gel substrates) (page 18, lines 25-30; page 19, lines 15-17; FIG. 1).
Regarding claim 12, Wagner teaches adding DMEM to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate and allowing the blood-platelet-lysate-medium to gelatinize at approximately 37 °C therefore obtaining a gelled substrate comprising blood platelet lysate (page 5, lines 12-28, to page 6, lines 1-8), thus meeting the limitation of claim 12.
Regarding amended claim 14 and the limitation “wherein the gelatinization-inhibiting substance is heparin”, it is noted, as set forth above regarding claim 1, Wagner teaches the blood platelet lysate, either pure or diluted, spontaneously gelatinizes at approximately 37 °C (page 5, lines 22-25). Wagner specifically teaches the three-dimensional, gel-like substrate comprising the blood platelet lysate is substantially devoid of a gelatinization-inhibiting substance, such as heparin (page 3, lines 13-16; page 6, lines 10-13; and page 15, lines 6-8). Thus, Wagner’s teaching reads on “wherein the gelatinization-inhibiting substance is heparin”, thus meeting the limitation of claim 14.
Regarding claims 15-17 and the limitations directed to the concentration of the platelet lysate, it is noted as set forth above regarding claim 12, Wagner teaches Wagner teaches adding DMEM to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate (claimed range lies within the prior art range) (page 5, lines 12-28, to page 6, lines 1-8), thus meeting the limitation of claims 15-17.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Regarding claims 21 and 22, Wagner’s teaching at pages 5-6 does not further comment on whether or not whether or not the thrombocyte concentrate comprising platelets was supplemented with Acid-Citrate-Dextrose (ACD). However, Wagner (page 14, lines 20-25) further teaches processing and concentrating platelets to produce a 200 mL platelet concentrate supplemented with Acid-Citrate-Dextrose (ACD), prior to lysing the platelets to produce a platelet lysate.
Thus, Wagner does render obvious providing a thrombocyte concentrate comprising platelets supplemented with Acid-Citrate-Dextrose (ACD), that is, Wagner teaches the limitations required by the current claims and as all limitations are found in one reference it is held that a method for producing a platelet lysate by providing a thrombocyte concentrate comprising platelets supplemented with Acid-Citrate-Dextrose (ACD), is within the scope of the teachings of Wagner, and thus renders the invention of claim 1 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to provide a thrombocyte concentrate comprising platelets supplemented with Acid-Citrate-Dextrose (ACD). Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Wagner.
Regarding claim 23, it is noted that claim 23 depends directly from claim 11, and thus depends indirectly from claim 10. As set forth above at the rejection of claim 10, it is noted that the limitations directed to the cultivation of cells are directed to the intended use of the platelet lysate product produced by the claimed method. Claim 23 recites the limitation “wherein the lyophilization has no effect on a differentiation potential and immunophenotype profile of the MSCs”. For the reasons discussed above regarding claims 10 and 11, this limitation is also directed to the intended use of the product produced by the claimed method.
As such, claim 23 does not further limit claims 10 or 11, and is included in the rejection of claim 11.
Rejection Maintained
Claims 1-5, 10-12, 14-17 and 21, and new claims 22-23, are rejected under 35 U.S.C. 103 as being unpatentable over Wagner et al., (WO 2013/000672, previously cited; IDS 1/11/2019) (“Wagner”), in view of Houze et al., (WO 2013/076507; IDS 1/11/2019) (“Houze”).
The rejection has been updated in view of Applicant’s claim amendment submitted January 10, 2023.
Regarding claim 1, Wagner is directed to a method for cultivating cells (mesenchymal stromal cells or fibroblasts) on/in the surface of a three-dimensional gelled scaffold comprising 1-60% human platelet lysate (HPL) (page 3, lines 8-20). Wagner teaches a two-phase system comprising (a) a liquid medium and (b) a three-dimensional, gel-like substrate. The three-dimensional, gel-like substrate comprises blood platelet lysate and is free of a gelatinization-inhibiting substance, e.g. heparin (page 3, lines 13-15; page 15, lines 7-8; FIG. 8A). The liquid medium comprises the blood platelet lysate in combination with a gelatinization-inhibiting substance (page 6, lines 10-13).
Wagner (page 5, lines 12-28, to page 6, lines 1-8) specifically teaches the following method:
a) Providing a thrombocyte concentrate, reads on “providing a thrombocyte concentrate comprising platelets”;
b) Harvesting blood platelets from said concentrate;
c) Lysing said platelets, reads on “lysing the blood platelets so as to produce a platelet lysate”;
d) Adding at least one medium component to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate; and
e) Allowing the blood-platelet-lysate-medium to gelatinize at approximately 37 °C so as to obtain a gel-like substrate (i.e. three-dimensional substrate, see FIG. 1) comprising blood platelet lysate (HPL-gel substrate).
Thus, Wagner’s method reads on “A method for producing a material for preparing a three-dimensional substrate for cultivating cells”.
Wagner teaches the blood platelet lysate, either pure or diluted, spontaneously gelatinizes at approximately 37 °C (page 5, lines 22-25). Wagner specifically teaches the three-dimensional, gel-like substrate comprising the blood platelet lysate is substantially devoid of a gelatinization-inhibiting substance (page 3, lines 13-16; page 6, lines 10-13; and page 15, lines 6-8). Thus, Wagner’s disclosed three-dimensional platelet lysate gel-material reads on, “…being free of any gelatinizing-inhibiting substance…”.
Wagner further teaches the medium component comprises a standardized medium composition for cell culture, e.g. DMEM low glucose (DMEM-LG). Wagner further teaches the culture medium contains essential growth factors and all necessary nutrients for cell cultures without undesired serum components. Furthermore, the substrate may comprise 1 -40 % blood platelet lysate, specifically the gel-like substrate according to the invention may comprise 10 % HPL (human platelet lysate), 89 % DMEM, and 2mM L-glutamine (page 5, lines 26-28 to page 6, lines 1-8).
Further regarding claim 1, it is noted that Wagner does not further teach lyophilization of the platelet lysate prior to addition to the culture medium for preparing the gel-like substrate. However, Houze is directed to a method of preparing a platelet lysate composition for therapeutic use (Abstract). Houze (Fig. 1) illustrates the platelet lysate is lyophilized, and thereafter used to prepare the platelet-rich gel that is subsequently seeded with stem cells (page 18, lines 25-28). Houze teaches lyophilization of the platelet lysate composition produces a stabilized, freeze-dried powder that contains growth factors which are useful in wound healing (page 6, lines 23-26), and lyophilization of the platelet lysate provides the advantage of longer shelf-life, easy storage and handling since it can be kept in a small place, and has the further advantage of being applied in a formulation such as a gel (page 19, lines 29-31 to page 20, lines 1-4).
Houze further teaches the lyophilized platelet lysate composition can be combined with water just prior to use and a gel-like product will be formed, and the composition can be combined with mesenchymal stem cells (page 23, lines 14-25).
Thus, Houze has established it was well-known in the art to prepare platelet lysate compositions by lyophilization in order to provide a product that is easier to store, has the advantage of a longer shelf-life and is a readily available off-the-shelf product that is useful as a cell culture substrate that provides beneficial growth factors and cytokines.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to lyophilize the platelet lysate of Wagner in order to provide a stable product having a long shelf-life that can be easily stored and thus does not require expensive storage conditions, as well as being readily available at the time of need, thus permitting the advance preparation of the product.
The person of ordinary skill in the art would have been motivated to modify the method of Wagner to include lyophilizing the platelet lysate, as taught by Houze, for the predictable result of successfully preserving the platelet lysate in a manner that permits long shelf-life, cost-cutting storage and advance preparation, therefore being readily available at the time of need, thus meeting the limitation of claim 1.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Wagner and Houze because each of these teachings are directed at using platelet lysates in cell culture as well as for therapeutic uses.
Further regarding claims 1 and 10 and the limitations “wherein the lyophilized dry platelet lysate material is configured to be reconstituted by addition of water at a place of use resulting in spontaneous gelatinization without addition of a coagulation-inducing agent” (claim 1) and “preparing the three-dimensional substrate for cultivating cells by adding water to the lyophilized dry material at a place of use, wherein the lyophilized dry material spontaneously gelatinizes due to the absence of any gelatinizing-inhibiting substance” (claim 10), it is noted, as discussed above at Claim Interpretation, the claims do not positively recite an active step of adding water to produce spontaneous gelatinization. This limitation is directed to the intended use of the produced lysate material “at a place of use”, which does not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
Regarding claims 2-4, it is noted Wagner teaches adding at least one standardized medium composition for cell culture, specifically DMEM, to obtain a medium comprising 1-60% blood platelet lysate, thus meeting the limitation of claims 2-4.
Regarding claim 5, as set forth above regarding claim 1, Wagner teaches platelet lysates can be generated by a simple freeze-thaw process (page 1, lines 24-25), thus meeting the limitation of claim 5.
Regarding claims 10 and 21, and the limitations directed to preparing a three-dimensional substrate for culturing cells, it is noted as set forth above regarding claim 1, the combined prior art teaches providing a platelet lysate material by:
a) Providing a thrombocyte concentrate comprising platelets supplemented with ACD;
b) Harvesting blood platelets from said concentrate;
c) Lysing the blood platelets to provide a platelet lysate material comprising blood platelet lysate; and
d) Lyophilizing the platelet lysate to provide a lyophilized dry material which is free of any gelatinization-inhibiting substance, specifically heparin, which is prepared by:
providing a thrombocyte concentrate comprising platelets supplemented with ACD;
lysing the blood platelets to produce a platelet lysate;
lyophilization of the platelet lysate to provide the lyophilized dry material, and preparing the three-dimensional substrate for cultivating cells by adding an aqueous medium (DMEM) or saline (i.e. adding water to the lyophilized dry material at a place of use).
As to the limitation “preparing the three-dimensional substrate for cultivating cells” it is noted, as set forth above regarding claim 1, Wagner teaches adding DMEM to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate; and allowing the blood-platelet-lysate-medium to gelatinize at approximately 37 °C therefore obtaining a gelled substrate (i.e. preparing the three-dimensional substrate) comprising blood platelet lysate. Cells were thereafter seeded on the HPL gel (human platelet lysate gel) (FIG. 1 and page 5, lines 12-28, to page 6, lines 1-8; page 18, lines 25-30; page 19, lines 15-17), thus the combined prior art meets the limitations of claims 10 and 21.
Regarding claim 11 and the limitation “wherein the cells are mesenchymal stromal cells”, it is noted, as discussed above regarding claim 10, the limitation “for cultivating cells” is directed to the intended use of the product produced by the instant method, that is “at a place of use” water will be added to form the three-dimensional substrate for cultivating the cells. Claim 10 does not recite an active step of adding cells. Therefore, the recited mesenchymal stromal cells (MSCs) are also directed to the intended use of the product produced by the claimed method.
As such, claim 11 does not further limit parent claim 10, and is included in the rejection of claim 10.
However, it is noted that Wagner teaches seeding mesenchymal stem cells (MSCs) on the HPL-gel substrates (platelet lysate gel substrates) (page 18, lines 25-30; page 19, lines 15-17; FIG. 1).
Regarding claim 12, Wagner teaches adding DMEM to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate and allowing the blood-platelet-lysate-medium to gelatinize at approximately 37 °C therefore obtaining a gelled substrate comprising blood platelet lysate (page 5, lines 12-28, to page 6, lines 1-8), thus meeting the limitation of claim 12.
Regarding amended claim 14 and the limitation “wherein the gelatinization-inhibiting substance is heparin”, it is noted, as set forth above regarding claim 1, Wagner teaches the blood platelet lysate, either pure or diluted, spontaneously gelatinizes at approximately 37 °C (page 5, lines 22-25). Wagner specifically teaches the three-dimensional, gel-like substrate comprising the blood platelet lysate is substantially devoid of a gelatinization-inhibiting substance, such as heparin (page 3, lines 13-16; page 6, lines 10-13; and page 15, lines 6-8). Thus, Wagner’s teaching reads on “wherein the gelatinization-inhibiting substance is heparin”, thus meeting the limitation of claim 14.
Regarding claims 15-17 and the limitations directed to the concentration of the platelet lysate, it is noted as set forth above regarding claim 12, Wagner teaches Wagner teaches adding DMEM to the lysate so as to obtain a medium comprising 1 -60 % blood platelet lysate (claimed range lies within the prior art range) (page 5, lines 12-28, to page 6, lines 1-8), thus meeting the limitation of claims 15-17.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Further regarding claims 21-22, Wagner’s teaching at pages 5-6 does not further comment on whether or not whether or not the thrombocyte concentrate comprising platelets was supplemented with Acid-Citrate-Dextrose (ACD). However, Wagner (page 14, lines 20-25) further teaches processing and concentrating platelets to produce a 200 mL platelet concentrate supplemented with Acid-Citrate-Dextrose (ACD), prior to lysing the platelets to produce a platelet lysate.
Thus, Wagner does render obvious providing a thrombocyte concentrate comprising platelets supplemented with Acid-Citrate-Dextrose (ACD), that is, Wagner teaches the limitations required by the current claims and as all limitations are found in one reference it is held that a method for producing a platelet lysate by providing a thrombocyte concentrate comprising platelets supplemented with Acid-Citrate-Dextrose (ACD), is within the scope of the teachings of Wagner, and thus renders the invention of claim 1 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to provide a thrombocyte concentrate comprising platelets supplemented with Acid-Citrate-Dextrose (ACD). Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Wagner.
Regarding claim 23, it is noted that claim 23 depends directly from claim 11, and thus depends indirectly from claim 10. As set forth above at the rejection of claim 10, it is noted that the limitations directed to the cultivation of cells are directed to the intended use of the platelet lysate product produced by the claimed method. Claim 23 recites the limitation “wherein the lyophilization has no effect on a differentiation potential and immunophenotype profile of the MSCs”. For the reasons discussed above regarding claims 10 and 11, this limitation is also directed to the intended use of the product produced by the claimed method.
As such, claim 23 does not further limit claims 10 or 11, and is included in the rejection of claim 11.
Response to Remarks
Rejection under 35 USC 112:
Applicant’s amendment submitted January 10, 2023 obviates the previous rejection of claim 4.
Rejections under 35 USC 103:
Applicant has traversed the rejection of record on the grounds that Patel reconstitutes the lyophilized platelet lysate in DMEM and collects the platelet concentrate in the presence of an anticoagulant (e.g. heparin), which is a feature that is excluded from the claims as currently written, as discussed at Applicant’s remarks (first paragraph, page 8).
Applicant’s remarks have been carefully considered, but are not found persuasive.
In response to reconstitution in DMEM, it is noted as discussed above at Claim Interpretation, the limitations directed to adding water/reconstitution, are intended use limitations directed to the intended use of the produced lysate material “at a place of use”, which does not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
As to the exclusion of the presence of an anticoagulant when collecting the thrombocyte concentrate, it is noted that, although claims 1 and 10 have removed, by striking through, the limitations directed to supplementing the thrombocyte concentrate with ACD, it is noted the instant claims employ the transitional phrase “comprising”. The transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“[L]ike the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended.”). “The word ‘comprising’ transitioning from the preamble to the body signals that the entire claim is presumptively open-ended.” Id. MPEP 2111.03
It is further noted, as discussed above at Claim Interpretation regarding the phrase “… lyophilized dry platelet lysate material being free of any gelatinizing-inhibiting substance…”, Applicant’s specification (page 8, lines 14-21 and page 9, lines 11-20) discloses the human platelet lysate is generated by apheresis from plasma supplemented with the anticoagulant Acid-Citrate-Dextrose (gelatinizing-inhibiting substance). Thereafter, the lyophilized platelet lysate is reconstituted without the addition of gelatinization-inhibiting substances such as heparin in order to permit spontaneous gelatinization (coagulation) due to the calcium that is present in the solvent used for reconstitution (specification at page 9, lines 32-33; and page 15, lines 29-31). Therefore, given Applicant’s specification discloses the lyophilized platelet lysate is prepared without the addition of any exogenous gelatinization-inhibiting substances such as heparin, this limitation is interpreted to exclude the addition of exogenous anticoagulants to the lyophilized platelet lysate. In view of Applications specification, this limitation does not exclude the use of anticoagulants for collection or generation of platelets from plasma.
As to Applicant’s remarks regarding the “configured to” language and the consideration of functional language, as discussed at Applicant’s remarks (second full paragraph, page 8), Applicant’s remarks have been fully considered, but are not found persuasive.
In response, it is noted as set forth above at Claim Interpretation, the limitations recited following “configured to” are directed to the intended use of the product produced by the claimed method, that is ‘reconstituted….at a place of use’. It is noted the claim does not positively recite an active step of adding water to produce spontaneous gelatinization. This limitation is directed to the intended use of the produced lysate material “at a place of use”, which does not further define or limit the method of producing a platelet lysate material. See MPEP 2111.02
Applicant further disagrees that the skilled artisan would have had a reasonable expectation of success in combining the teachings of Wagner and Patel, and asserts the Office has not articulated why it doubts Applicant’s disclosure at page 3, starting at line 24, as discussed at Applicant’s remarks (first and second paragraphs, page 9).
Applicant’s remarks have been fully considered, but are not found persuasive.
In response, it is first noted Applicant’s disclosure at page 3 recites the following:
“Surprisingly,