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 .
Status of Claims
Claims 11-30 are pending.
Priority
Claims 11-30 are a 371 of PCT/CH 2022/117997 filed on September 9, 2022, which has priority to CHINA 2022 1021797.5 filed on March 8, 2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on October 10, 2024, was filed before the mailing of the First Office Action on August 1, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
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 20 and 30 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.
Claim 20 recites “forming the human platelet-derived apoptotic vesicles on a surface”. The specification does not define what is meant by “forming” in the context of claim 20. It is unclear where the claim requires generating apoptotic vesicles on the scaffold itself, depositing or coating previously isolated apoptotic vesicles, or some other process associated with adhering the apoptotic vesicles to the scaffold. As such, a person of ordinary skill would not be able to determine the metes and bounds of the claim.
Claim 30 recites “wherein the human platelet-derived apoptotic vesicles are derived from platelets of a subject”. However, the specification neither defines or describes the term “subject”. It is unclear what “subject” is referring to. Is the term “subject” referring to an autologous source, another human donor, or some other donor. Moreover, claim 30 already recites that the platelets are derived from a human. It is unclear what limitation “subject” is imparting on claim 28 given the claim language in both 28 and 30 clearly state that the platelets are derived from a human.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 11-30 are rejected under 35 U.S.C. §103 as being unpatentable over Rossello et al. [Platelet-derived extracellular vesicles promote osteoinduction of mesenchymal stromal cells, Bone Biology, 2020], in view of Zhou et al. [CN 113943705 A, January 2022], in view of Hass et al. [Different populations and sources of human mesenchymal stem cells (MSC): a comparision of adult and neonatal tissue-derived MSC, Cell Commun Signal, 2011], in view of Kang et al. [Exosome-functionalized magnesium-organic framework-based scaffolds with osteogenic, angiogenic and anti-inflammatory properties for accelerated bone regeneration, Bioactive Materials, February 18 2022], in view of Xu et al. [Poly(Dopamine) coating on 3D-printed poly-lactic-co-glycolic acid/Beta-tricalcium phosphate scaffolds for bone tissue engineering, Molecules, 2019].
Regarding claim 11 for a method of promoting osteogenic differentiation of mesenchymal stem cells comprised of culturing the mesenchymal stem cells under the presence of human platelet-derived apoptotic vesicles, Rosselo et al. teaches that human platelet-derived extracellular vesicles interact with mesenchymal stromal cells, including mesenchymal stem cells, and promote differentiation toward osteogenic lineage [Introduction]. Rossello et al. further teaches that platelet-derived vesicles enhance osteogenic differentiation, including increased expression of osteogenic markers that include RUNX2 [Discussion ¶ 2, pg. 671-672]. This establishes that platelet-derived vesicles were recognized as biologically active mediators capable of driving osteogenesis in mesenchymal stem cells. Furthermore, even though Rossello et al. is using umbilical cord derived mesenchymal stromal cells, Hass et al. teaches that bone marrow-derived mesenchymal stem cells are the most common type of mesenchymal stem cell used for investigation [Adult MSC: source, isolation and culture]. Hass et al. also teaches that mesenchymal stem cells, regardless of origin, share very similar machinery [Cell surface marker expression].
With respect to the limitation where the mesenchymal stem cells are cultured in the presence of human platelet-derived apoptotic vesicles, Zhou et al. discloses the use of apoptotic vesicles for promoting adipogenic differentiation of mesenchymal stem cells [Para starting with “The present invention further provides the application of the above-mentioned apoptotic microvesicles”]. Although the apoptotic vesicles in Zhou et al. were derived from mouse mononuclear macrophage leukemia cells, both exosome/extracellular vesicles and apoptotic vesicles are subclasses of extracellular vesicles that are known to transport protein, lipids, mRNA, miRNA, and other signaling molecules. Additionally, both references show the biological effect of vesicle mediated communication. Lastly, as stated by Rossello et al., bone marrow-derived mesenchymal stem cells are well known for their dependence on RUNX2 for being a master regulator of osteoblast lineage commitment [Discussion ¶ 1, pg. 672]. And although Zhou et al. is directed to adipose-derived mesenchymal stem cells, a person of ordinary skill in the art could necessarily expect the differentiation-promoting activity of apoptotic vesicles seen in Zhou et al. could be applied to bone-derived mesenchymal stem cells. This is especially true given that Rossello et al. discloses that platelet-derived extracellular vesicles are known to drive osteogenic differentiation in mesenchymal stromal cells by increasing RUNX2 activation which is known as the master regulator for driving differentiation towards a osteogenic state. Based on this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Rossello et al. where the authors were able to show an increase in osteogenic differentiation in mesenchymal stromal cells in the presence of platelet-derived extracellular vesicles that included apoptotic vesicles with the teachings of Zhou et al. where the authors used apoptotic vesicles, a subclass of extracellular vesicles, to direct mesenchymal stem cells towards an adipogenic state. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would be able to derive osteoblasts from mesenchymal stem cells by culturing these mesenchymal stem cells in the presence of human platelet-derived apoptotic vesicles given that Rossello et al. teaches that platelet-derived vesicles achieve osteogenesis through increased RUNX2 expression with the teachings of Zhou et al. where apoptotic vesicles, also an extracellular vesicle subtype, is also capable of directing mesenchymal stem cell differentiation would lead to an increase in RUNX2 expression given that Rossello et al. already showed the platelet-derived extracellular vesicles significantly increased RUNX2 expression.
For claim 12 where the mesenchymal stem cells are bone marrow mesenchymal stem cells, Hass et al. discloses that human bone marrow-derived mesenchymal stem cells where the most commonly utilized mesenchymal stem cell [Adult MSC: source, isolation and culture].
For claim 13 where the mesenchymal stem cells are human, again, Hass et al. discloses that human bone marrow-derived mesenchymal stem cells are the “gold standard” [Id.].
For claim 14 where the human platelet-derived apoptotic vesicles promote osteogenic differentiation in mesenchymal stem cells by upregulating RUNX2 gene expression in mesenchymal stem cells, see analysis for claim 11.
For claim 15 where the apoptotic vesicles are biconcave and disc shaped with a particle size of 90 nm to 300 nm, Zhou et al. discloses that the apoptotic microvesicles are in the shape of a biconcave disc with a particle size of 150-600 nm with an average particle size of 240 nm for the apoptotic microvesicles [Para starting with “the present invention also provides apoptotic microvesicles prepared according to the above-mentioned”].
For claim 16 where the apoptotic microvesicles are isolated and purified in vitro and resuspended in the presence of staurosporine and then collecting a supernatant using gradient centrifugation, Zhou et al. teaches an adding staurosporine to induce cell apoptosis followed by collecting the supernatant from the culture medium using gradient centrifugation in order to obtain the apoptotic microvesicles [Para starting with “1) in vitro culture of mouse mononuclear macrogphage leukemia cell line;” parts 1, 2, and 3].
For claim 17 where the method further involves culturing in a minimum essential medium containing 10% FBS, 1% penicillin-streptomycin dual antibiotic, Zhou et al. further teaches the preferred medium is DMEM, i.e. a minimum essential medium, that contains 10% FBS and 1% penicillin-streptomycin double antibiotic [Para starting with “Preferably, the medium for in vitro culture is: DMEM”].
For claim 18 where the gradient centrifugation is centrifuging the supernatant at 4˚ C and 800 g for 10 min to obtain a first centrifugation supernatant followed by a centrifugation at 4˚ C and 16,000 g for 30 minutes to obtain crude apoptotic vesicles, Zhou et al. teaches in part “a)” centrifuging the culture supernatant at 800 g for 10 minutes at 4˚ C to obtain the first centrifugal supernatant and also centrifuging the supernatant at 16,000 g for 30 minutes at 4˚ C to obtain crude apoptotic microvesicles [Para starting with “In one embodiment according to the present invention, the gradient centrifugation method”]. Claim 18 further states to wash the crude apoptotic vesicles in PBS and centrifuge for 30 minutes at 16,000 g at 4˚ C. Zhou et al. also teaches this step at part d) where it states “wash the crude apoptotic microvesicles with sterile PBS, and then centrifuge at 16000 g for 30 min at 4˚ C. to obtain pure apoptotic microvesicles”.
For claim 19 where promoting osteogenic differentiation in mesenchymal stem cells is further used in repairing a bone defect, Qi et al. teaches the use of mesenchymal stem cells were used where the hiPSC-MSCs and bone marrow-derived MSCs were directed towards osteogenesis differentiation in order to promote bone regeneration through enhanced angiogenesis [Abstract, Introduction pg. 837 R column ¶ 2].
Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Rossello et al. that used platelet-derived extracellular vesicles to drive osteogenesis in mesenchymal stromal cells with the teachings of both Hass et al. that disclosed bone marrow-derived mesenchymal stem cells are often the most utilized stem cell for research purposes with the teachings of Zhou et al. that disclosed the use of apoptotic microvesicles for enhancing differentiation in adipose-derived mesenchymal stem cells with the additional teachings of Qi et al. that disclosed the use of bone marrow-derived stem cells being explored for use in bone regeneration where mesenchymal stem cells were differentiated into osteogenesis through the use of exosomes. Based on this, there was a reasonable expectation of success that a person of ordinary skill in the art could take the teachings of Rossello et al. and combine it with the teachings of Hass et al. and Zhou et al. to culture mesenchymal stem cells in the presence of human platelet-derived apoptotic vesicles given that both Rossello et al. and Zhou et al. disclose culturing mesenchymal cells in the presence of extracellular vesicles that include apoptotic vesicles where the mesenchymal cells were human bone marrow-derived mesenchymal stem cells with the additional teachings of Qi et al. that further teaches the use of such mesenchymal stem cells to be used in promoting bone regeneration.
For claim 20 where the bone defect formulation involves forming the apoptotic vesicles on a surface of PLGA scaffold, Kang et al. discloses PLGA nanostructure scaffolds were synthesized where exosomes were deposited on the scaffolds [Highlights]. Here, there is a reasonable expectation of success that a person of ordinary skill would recognize the teachings Kang et al. could be combined with the isolated apoptotic vesicles taught by Zhou et al. given that apoptotic vesicles are a subgroup of exosomes where the artisan would recognize that exosomes and/or apoptotic vesicles were capable of being deposited on a PLGA scaffold.
For claim 21 where the human platelet-derived apoptotic vesicles are autologous, both Zhou et al. and Rossello et al. discuss the use of autologous cells and the benefits [Para starting with “autologous fat filling”, Introduction ¶ 1, respectively].
For claim 22 wherein the PLGA scaffold has a diameter of 4mm and a height of 2mm, Kang et al. in the provided supplemental materials discloses a PLGA synthesized scaffolds that had diameters of 6.5mm up to 1.5 cm with a thickness of 1mm. [Figure S10 Supplemental Material]. Additionally, MPEP § 2144.05 states that “…a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close” citing Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Here, Kang et al. discloses a thickness of 1mm and Applicant discloses a thickness of 2mm. Based on this, it would have been prima facie obvious for a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Kang et al. to recognize PLGA scaffolding could be formulated into various sizes including multiple diameters as well as thickness height to include 2mm as claimed by Applicant.
For claim 23 where the PLGA scaffold is soaked in a polydopamine solution, then removing the unattached dopamine leaving a PLGA/pDA scaffold, Xu et al. discloses a method for soaking a PLGA scaffold in polydopamine coating where the authors used an easy one step method [Introduction ¶ 3]. This combined with Kang et al. where exosomes were deposited on PLGA scaffolds [Highlights]. There would have been a reasonable expectation of success that a person skilled in the art would have recognized the teachings of both Kang et al. and Xu et al. where extracellular vesicles, including apoptotic vesicles, could be deposited on a PLGA scaffold that was soaked in polydopamine given that the surface wettability of polydopamine coated scaffolds is better than uncoated scaffolds [Xu et al., Discussion ¶ 1]. Additionally, Xu et al. discloses using centrifugation as a means of removing excess polydopamine [4.2 PDA Coating], and lastly, Xu et al. discloses soaking MC3T3-E1 cells with the sterilized scaffolds where the scaffolds were transferred into 96-well plates with the cells being cocultured with PDA and later adding CCK-9 solution [Cell culture on scaffolds].
For claim 24 where the PLGA soaked in a dopamine solution for 18 hours at 37˚ C under shaking conditions, Xu et al. discloses culturing the PGLA scaffold in dopamine overnight, but Xu et al. uses low rpm centrifugation, i.e. 150 rpm, instead of Applicant’s claimed “shaking”. However, Applicant’s “shaking” during incubation would have been an obvious matter of routine process optimization given that gentle agitation, shaking, rocking, or similar mixing techniques are employed during solution-phase coating processes in order to improve uniform exposure to the coating solution. Substituting shaking for another form of gentle mixing and/or static overnight incubation would have led to predictable results where formation of a PDA-coated PLGA scaffold was created.
For claim 25 where the PLGA/pDA scaffold is then sterilized and washed, Xu et al. teaches using ultrapure water for washing followed by sterilizing the scaffolds using UV radiation and 75% ethanol for 2 hours [4.4 Cell culture on scaffolds]. Xu et al. further discloses washing the osteogenesis assay three times with PBS [4.5 Osteogenesis Assay].
For claim 26 where the concentration of the dopamine solution is 2mg/mL, Xu et al. teaches that the scaffold was coated with a 2mg/mL PDA solution and was abbreviated as PDA2 [4.2. PDA coating].
For claim 27 where the concentration of the human platelet-derived apoptotic vesicles in the solution comprising the human platelet-derived apoptotic vesicles is 500 ng/µL, The 500 ng/µL human platelet-derived apoptotic vesicles would have been an obvious matter of routine optimization because the concentration of biologically active agents used in cell culture is a recognized result-effective variable. MPEP § 2144.05(II)(A) states “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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)”.
For claim 28 where a bone defect repair formulation that comprises human platelet-derived apoptotic vesicles on a PLGA scaffold, Both Kang et al. and Xu et al. discuss the use of PLGA scaffolds where exosomes and/or cells are deposited on scaffolds for bone regeneration [Abstract, 4.4 Cell Culture on Scaffolds, respectively] and Xu et al. teaching a method of coating the PLGA scaffold with a polydopamine coating that increases the wettability of the PLGA scaffold could be combined with the teachings of Rossello et al. and Zhou et al. where combined it teaches the use of human derived platelets are used to isolate extracellular vesicles, including apoptotic vesicles, in use of directing mesenchymal stem cells to an osteogenesis state given that Rossello et al. specifically discusses the use of these cells in bone regeneration [Introduction ¶ 1]. Given this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Rossello et al. and Zhou et al. where both disclose using extracellular vesicles to direct mesenchymal cell fate that included osteogenesis with the teachings of Kang et al. that discloses a method for depositing exosomes onto a PLGA scaffold where a reasonable person of ordinary skill would recognize that isolated apoptotic vesicles, which are a subunit of extracellular vesicles, could also be deposited on a PLGA scaffold in order to promote osteogenesis in mesenchymal stem cells with the additional teachings of Xu et al. that discloses a method for making PLGA scaffolds that have been optimized for cell particle deposit.
For claim 29 wherein the bone defect repair formulation is made up of the PLGA scaffold that has a polydopamine membrane with human platelet-derived apoptotic vesicles on the pDA membrane, see the analysis for both claims 11 and 28.
For claim 30 where the human apoptotic vesicles are derived from platelets of a subject, both Rossello et al. and Zhou et al. both disclose cells and/or platelets can be autologous [Introduction ¶ 1, Para starting with “autologous fat filling”] thereby inferring the cells are both human and can be autologous.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Rossello et al. with the teachings of Zhou et al. where Rossello et al. teaches using platelet derived extracellular vesicles and culturing mesenchymal stromal cells in order to steer differentiation towards osteogenesis with the teachings of Zhou et al. that discloses further isolating apoptotic vesicles which are a subclass of extracellular vesicles that can be isolated from apoptosis induced platelets with the additional teachings of how to isolate and culture the apoptotic vesicles as taught by Zhou with the additional teachings of Kang et la. and Xu et al. that would direct an Artisan to deposit the isolated apoptotic vesicles on a prepared PLGA scaffold that contains a polydopamine coating where bone marrow-derived mesenchymal stem cells could be seeded on the PLGA/pDA scaffold with deposited apoptotic vesicles in order to steer the bone marrow-derived mesenchymal stem cells, as taught by Hass et al., towards an osteogenic fate that can then be used in a bone regeneration formulation scaffold where the platelets and/or mesenchymal stem cells are harvested directly from the patient potentially receiving the bone regeneration scaffold. Based on this, there would have been a reasonable expectation of success that a person of ordinary skill would have recognize the teachings of Zhou et al. and Rossello et al. and combined them with the teachings of Kang et al. and Xu et al. to create a polydopamine coated PLGA scaffold where apoptotic vesicles were deposited for use in a bone regeneration scaffold where the platelet-derived apoptotic vesicles and/or mesenchymal stem cells were harvested from the same patient.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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