DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/2/2025 has been entered.
Claims status
Claims 1-5 is/are currently pending with claims 1-4 is/are withdrawn. Claims 5 is/are under examination.
Withdrawn Objections
The objections presented herein represent the full set of objections currently pending in this application. Any objections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 112(b)
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.
Claim 5 is 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 5 recites “adding exosome isolation solution containing biphasic PEG-Dextran for septal cartilage exosome isolation from the culture medium of step (1)”. The phrase “the culture medium of step (1)” lacks sufficient antecedent basis, since the claim does not recite a step (1), only a step (i). Further, it is unclear what the “biphasic PEG-Dextran” is being added to “for” the purpose of “septal cartilage exosome isolation from the culture medium of step (1)”. It could be interpreted that the biphasic PEG-Dextran is being added to the culture medium from step (i). However, this interpretation does not appear to be supported by the instant specification and the prior art since it would result in addition of the PEG-Dextran solution before removal of the waste cells from the culture medium from step (i). The centrifugation of culture medium at 300g for 10 minutes performed in step (ii)(b) removes waste cells present in the culture medium. PEG-Dextran is added to the culture medium from which waste cells are already removed to separate exosomes from the proteins and other small molecule components of the culture medium. This is supported by the specification (page 19, para 2: points 3-5 in the list) and is also supported by the prior art. For example see Figure 1 and Methods: Preparation of extracellular vesicles and Aqueous two-phase system in Kim et al (PLoS ONE 10(6): e0129760. doi:10.1371/journal.pone.0129760, 2015) and see Materials and Methods Isolation of EVs from interstitial fluid and validation, EV-protein mixture, EV isolation in Shin et al (Scientific Reports | 5:13103, 2015; ref of record). Therefore, it could not be interpreted that the biphasic PEG-Dextran is being added to the culture medium from step (i) and thus it is unclear what the biphasic PEG-Dextran is being added to.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
New Matter
Claim 5 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. 37 CFR 1.118 (a) states that “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”.
Claim 5 has been amended to recite “adding exosome isolation solution containing biphasic PEG-Dextran for septal cartilage exosome isolation from the culture medium of step (1)”. As noted above, this amendment renders the claim indefinite. Furthermore, the original filed specification does not appear to support this amendment. The originally filed specification only states “The method of forming cartilage tissue from these isolated septal cartilage exosomes within the scope of the invention comprises the steps of “ and discloses “using exosome isolation solution containing biphasic PEG-Dextran for microvesicle isolation from the cells in the cultured medium” (page 19, para 2: point 2 in the list). Thus, the original specification does not recite “adding” biphasic PEG-Dextran before the centrifugation step of (ii)(b) which is performed to remove waste cells, normally performed prior to exosome isolation (see teachings from Kim and Shin noted in the 112b rejection above).
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure [or point to case law supporting incorporation of such a limitation as in the instant case]”.
Scope of Enablement
Claim 5 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification,
while being enabling for an in vitro method for generating chondrocytes by using exosomes derived from septal cartilage cells, wherein mesenchymal stem cells (MSCs) are differentiated into chondrocytes by in vitro culturing the MSCs in the presence of exosomes derived from septal cartilage cells,
does not reasonably provide enablement for a method wherein any stem cell type could be differentiated in chondrocytes or entire cartilage tissue.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: The claims as currently drafted appear to encompass a method of generating cartilage tissue by differentiating any type of stem cell into cartilage tissue wherein the differentiation step is performed in the presence of exosomes derived from cultured septal cartilage cells.
The specification does not define “cartilage tissue”. In the Background section, the specification notes that “Cartilage is a flexible, hard and white tissue that performs the function of bone in some organs” and “When tissue fluids reach the fibrous matrix of the cartilage, the chondroblasts are nourished” (page 1, para 3; page 2, para 1). Therefore, the specification teaches that cartilage tissue is a structurally flexible, hard and white tissue that comprises at least a fibrous matrix and chondroblasts and, performs structural functions similar to bone tissue in some organs. Prior teachings regarding cartilage tissue also teach that cartilage tissue is a tissue that comprises chondrogenic cells such as chondroblasts, chondrocytes and extracellular matrix components (Chang et al. Anatomy, Cartilage. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan; ref of record). Therefore, the broadest reasonable interpretation of the term cartilage tissue is a tissue that comprises chondroblasts, chondrocytes and extracellular matrix components and, displays functionality attributed to cartilage tissue. Therefore, claims encompass a method of generating a tissue that comprises chondroblasts, chondrocytes and extracellular matrix components using exosomes derived from septal cartilage, wherein the tissue generated functions as a cartilage tissue.
Therefore, the scope of the claim is expansive - wherein any stem cell type could be differentiated into entire cartilage tissue.
(B), (F), (G) The nature of the invention, the amount of direction and working examples provided by the applicant: The invention is in the field of generating cartilage. The specification suffers from numerous clarity issues such that it is hard to ascertain the type of cells used for differentiation into chondrocytes. Furthermore, only limited characterization of the cells produced from the differentiation step is provided.
Toxicity studies conducted using “septal exosomes” show that these exosomes do not affect viability of the cells used in this experiment (Page 7-8, bridging para; Figure 1). The examples do not specify the type of cells used or what “septal exosomes” are derived from.
Cartilage differentiation studies were conducted using “septal cell exosome” and/or “cartilage differentiation” solution (Page 8, para 2; Figure 2). Again, the example does not specify the type of cells used or what “septal exosomes” are derived from. Since this appears to be a differentiation protocol, an ordinary artisan would interpret the cell type used as a type of stem cell (totipotent, multipotent, pluripotent) however the experiment disclosed does not clearly identify the stem cell types that can be used.
In the description section, the specification present embodiments of the claimed method. Here in it states “The present invention relates to developing a formulation produced by the microvesicles that are released by the cells isolated from septal cartilage for generation of cartilage tissue.” (emphasis added, page 6, para 2). “One of the differences of the formulation of the present invention with respect to the state of the art is the use of cells isolated from septal cartilage and it makes a significant difference both in terms of where it is isolated from and in use of characteristically different cell types. Furthermore, within the scope of the invention, exosomes which are a special component of these cells are used” (emphasis added, page 6, last para). Therefore, although microvesicles and exosome are not the same (see Table 1 and Introduction-para 3 in Stahl et al, Pediatr Nephrol 2019; ref of record), it appears that exosomes of the claimed invention are derived from cells isolated from septal cartilage. Yet, no clear disclosure for the type of stem cell that was exposed to the exosomes can be ascertained.
In the cartilage differentiation experiment, the specification shows that the stem cells differentiate into cells that express CD44 and/or Sox9, markers of chondrocytes, only in the presence of the “septal cell exosome” (Figure 2A, B).
The specification does not provide any guidance regarding the stem cells used in the differentiation protocol. The specification does not provide any working examples wherein a cartilage tissue was generated.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: Chondrocytes are known to be differentiated from MSCs in vitro and in vivo, (see 1.3 Chondrogenesis in Griffiths (MicroRNA Regulation of Chondrogenesis in Human Embryonic Stem Cells. Thesis, The University of Manchester, 2016; ref of record) and Figure 1 in Cho et al (US 2017/0296590, Oct. 19, 2017; ref of record). However, several multipotent stem cells are known in the art such as at least mesenchymal stem cell, neural stem cells and hematopoietic stem cells. Thus, to the extent that the specification teaches use of exosomes to differentiate stem cells, the specification is not enabling because it does not disclose what type of stem cell can be differentiated into chondrocytes and/or cartilage by the claimed exosomes.
Regarding generation of chondrocytes using exosomes, Cho teaches a method of isolating exosomes from chondrocytes that were derived from stem cells (Figure 2) and the use of these exosomes to differentiate human adipose-derived stem cells, a type of MSC, into chondrocytes in vitro (Figure 6). Cho further shows that injection of their chondrocyte exosomes increases cartilage regeneration in vivo (Figure 7). Cho does not teach a method wherein any stem cells, other than MSC, could be used in their differentiation protocol or wherein stem cell differentiate into a cartilage tissue.
It remains unpredictable that exposure to exosomes from chondrocytes, including chondrocytes derived from septal cartilage, could differentiate any type of stem cell into chondrocytes, let alone entire cartilage tissue. Furthermore, it remains unpredictable if the method could be practiced in vivo.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims and the limited and unclear guidance in the specification. Although art enables a method of isolating exosomes from specific cell types and Cho shows exosomes isolated from chondrocytes that were derived from stem cells can be used to increase differentiation of human adipose-derived stem cells, a type of MSC, into chondrocytes, the art does not enable a method wherein exosomes increase differentiation of any stem cell into chondrocytes and wherein exosomes alone are capable of generating cartilage tissue. A skilled artisan is unable to practice this invention since the specification does not disclose critical details.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
After applying the Wands factors and analysis to claim 5, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher decisions discussed above, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure for the full scope of the claims and one of ordinary skill in the art would be burdened with undue experimentation to make and use the claimed invention within the broad scope as instantly claimed. Therefore, claim 5 is rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the claimed method within the broad scope as instantly claimed.
Claim Rejections - 35 USC § 103 - Maintained
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) 5 remains rejected under 35 U.S.C. 103 as being unpatentable over Cho et al (US 2017/0296590, Oct. 19, 2017; ref of record) in view of Amaral et al (Stem Cell Research (2012) 8, 292–299; ref of record), PCS-999-002 (Penicillin-Streptomycin-Amphotericin B Solution, commercially available from ATCC since at least 1999; ref of record), Arora (MATER METHODS 2013;3:175; ref of record) and Shin et al (Scientific Reports | 5:13103, 2015; ref of record).
Cho teaches a method of generating chondrocytes using exosomes [001]. In example 1, Cho teaches that exosomes are isolated from chondrocytes or chondroprogenitors, each of which are produced by in vitro differentiation of mesenchymal stem cells (Figure 2). During MSC differentiation into chondrocytes, exosomes were collected at day 14 when the differentiating cells display pre-cartilage condensation (=chondroprogenitor cell stage) and day 35 when differentiated chondrocytes are confirmed [0089-0090]. In example 3, Cho teaches differentiation of mesenchymal stem cells into chondrocytes by using chondrocyte-derived exosomes from example 1 wherein during the differentiation process the medium comprising exosomes is replenished every 3 days for 35 days (as required by step (iii)). Since 35 days comprise 10 days, Cho’s method comprises exosome administration every 3 days for 10 days which approaches the claimed range of exosome administration every 2 days for 10 days (as required by step (iii)). MPEP 2144.05 (I) 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. In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018) (the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.)”. Similarly, in the instant case, the claimed “every 2 days” is so similar to the taught “every 3 days” that a patentable distinction cannot be made. See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0). Thus, in teaching a method wherein exosomes are administered every 3 days, Cho renders the instantly claimed “every other day” prima facie obvious.
Although, Cho teaches isolating exosomes from chondrocytes, Cho does not teach isolating exosomes from chondrocytes that are from the septal cartilage. However, isolation of septal cartilage and culturing to produce chondrocytes was known in the art. Amaral teaches a method of culturing septal cartilage cells derived from human patient in alpha-MEM, 10% FBS, and, 100u/ml penicillin and 100ug/ml streptomycin as the antibiotics (Material and methods: Isolation and culture of cells) (as required by step (i)). Amaral teaches maintaining the cultures at 37°C in a humid atmosphere with 5% CO2 (i.e. maintaining the cultures in an incubator) (Material and methods: Isolation and culture of cells) (as required by step (i)).
Amaral does not use DMEM as culture base medium, 1%PSA as the antibiotic or exosome-depleted FBS in their protocol (as required by step (i)).
However, Arora teaches that alpha-MEM and DMEM are the commonly used cell culture medium for primary cell culture (Table 1) and an artisan performs routine optimization to select optimal media for their culture protocol based on type of cells to be cultured and also the purpose of the culture and resources available in the laboratory (page 5: Criteria for Selecting Media). Arora teaches that “In general, it’s always good to start with MEM for adherent cells” however “DMEM has almost twice the concentration of amino acids and four times the amount of vitamins as EMEM, as well as ferric nitrate, sodium pyruvate, and some supplementary amino acids.” (page 5, last para; page 6, para 4). Therefore, an ordinary artisan practicing the method of Amaral would optimize the cell culture medium based on various factors, picking between some of the most commonly used culture medium such as MEM (as taught by Amaral) or DMEM. In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions." See MPEP 2144.05(II).
Similarly, Penicillin-Streptomycin-Amphotericin Solution is a commercially available cell culture product for ATCC as taught by PCS-999-002. The product sheet for PCS-999-002 teaches the use of PSA at 1:100 (=1% v/v) (as required by step (i)). Substitution of 100u/ml penicillin and 100ug/ml streptomycin, as taught by Amaral, with 1% PSA, commercially available from ATCC as PCS-999-002, is prima facie obvious. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) See MPEP 2144.07. In the instant case, both 100u/ml penicillin and 100ug/ml streptomycin, as taught by Amaral, and 1% PSA, as claimed, perform the same intended function of reducing microbial contamination in cell culture (See Description in PCS-999-002 product sheet).
Furthermore, the use of exosome-depleted FBS in place of regular FBS when culturing Amaral’s septal cartilage cells for the purpose of deriving exosomes for use in Cho’s method is prima facie obvious based on the teachings of Shin. Shin teaches a method for producing EV-depleted FBS because FBS itself comprises large quantities of extracellular vesicles (EVs comprise exosomes; Introduction-line 1; Materials and Methods: EV-depleted fetal bovine serum preparation).
Taken together, Amaral teaches a method for culturing septal cartilage cells in MEM, 10%FBS and 100u/ml penicillin and 100ug/ml streptomycin at 37°C with 5% CO2, which renders the instantly claimed step (i) for culturing septal cartilage cells prima facie obvious based on the teachings of Arora, PCS-999-002 and Shin.
Regarding step (ii)(a-d), which recites process steps for generating the product of septal cartilage exosomes for use in the method of generating chondrocytes, these are product-by-process limitations since the active method only requires the product of septal cartilage exosomes for differentiating stem cells into cartilage cells. According to MPEP 2113, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”. In the instant case, the structure provided by the recited process is exosomes with a structure that allows for differentiating stem cells into cartilage cells. The method for producing the exosomes is immaterial or inconsequential to the operation of the method, absent showing of secondary considerations. Therefore, in teaching exosomes with a structure that allows for differentiating MSCs into chondrocytes, Cho meets these product-by-process limitations since Cho’s exosomes have the structure required for the method of differentiating MSCs into chondrocytes.
Therefore, it obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use Amaral’s human-derived septal chondrocytes in place Cho’s MSC-derived chondrocytes to produce exosomes for use in the method of differentiating MSCs into chondrocytes as taught by Cho. An ordinary artisan would be motivated to make such a substitution to identify other sources of exosomes, especially human relevant source such as taught by Amaral, that could be used in differentiating MSCs into chondrocytes. An ordinary artisan would reasonably expect that substituting exosomes derived from Amaral’s human-derived septal chondrocytes in place Cho’s exosomes would result in differentiating MSCs because Cho’s exosomes are also derived from chondrocytes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant’s arguments, see page 5, para 3, filed 6/3/2025, with respect to U.S.C.112a-Scope of Enablement rejection have been fully considered and are persuasive in part. Applicant argue that “Claim 5 is now amended to specify an in vitro method of generating cartilage tissue, it further defines that the septal cartilage exosome is isolated from septal cartilage cells” (page 5, para 3). Since this addresses one of the issues that lacked enablement (i.e. in vivo method), the instant 112a-Scope of Enablement rejection is now only directed to the remaining issues that were noted previously to lack enablement (i.e. stem cell type that is differentiation and the cell type/tissue generated).
Applicant's arguments filed 6/3/2025 regarding the U.S.C. 103 rejection of claim 5 have been fully considered but they are not persuasive.
Regarding Cho, Applicant argue that “Cho et al is discussing isolation of exosomes from stem cells differentiating into chondrocytes” and since “Exosomes derived from the stem cells differentiating into chondrocytes may carry materials that define the basic characteristic of stem cells, like growth factors, various bioactive proteins and genetic pertaining to cartilage cell differentiation (paragraphs 0029 and 0031). This is why Cho et al specifically uses exosome from stem cells differentiating into chondrocytes” (page 6, para 3). Further, Applicant argue that “On the other hand, the method of generating cartilage tissue according to claim 5 of the present patent application is using septal cartilage exosome isolated from septal cartilage cells” and allege that use of this specific chondrocyte source (i.e. septal cartilage) vs stem-cell derived chondrocytes of Cho “makes a significant difference [..] both in terms of where it is isolated from and in use of characteristically different cell types for exosome isolation (0038)’ (page 6, para 4). Applicant also allege without evidence that “Using the septal cartilage exosome isolated from septal cartilage cells for differentiation of stem cells is not only increasing cartilage tissue formation but also provides cartilage tissue with anti-inflammatory properties even though exosomes of the septal cells are not autologous (0039).” “This difference in using exosomes isolated from different cells in the method of the present patent application in relation to Cho et al is not only a novel but also inventive as the cartilage tissue prepared by the present patent application is providing the improved cartilage tissue having the anti-inflammatory properties. “ (page 6, para 6-7). This is not persuasive because Cho teaches that exosomes were collected from culture medium of the differentiating stem cells from 14 days to 35 days and while at 14 days chondrogenesis (i.e. chondrocyte formation) has started, it is done by day 35 (Figure 1, Example 1, [0089-90]). Therefore, in teaching isolating exosomes from stem cells that are already differentiated into chondrocytes (such as on at least day 35) and also isolating exosomes from stem cells differentiating into chondrocytes such that a portion of exosomes is derived from chondrocytes (such as on at least days 14-35), Cho teaches isolating exosomes derived from chondrocytes. Furthermore, Cho shows that exosomes isolated from MSCs are not as effective at inducing chondrogenesis as are exosomes isolated from a population of cells that comprise chondrocytes (i.e. a population of stem cells differentiating into chondrocytes from day 14-35; Figure 5). Thus, Cho teaches a method for generating chondrocytes by exposing MSCs to exosomes derived chondrocytes. Indeed, Cho does not teach culturing septal cartilage chondrocytes and thus does not derived exosomes from septal cartilage chondrocytes, however Amaral rectifies this deficiency by teaching septal cartilage chondrocytes (as noted in the rejection of record). Applicant do not present any argument pertaining to Amaral and more importantly pertaining to the combination of Cho and Amaral. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding allegations that exosomes isolated specifically from septal cartilage results in “increasing cartilage tissue formation” and “provides cartilage tissue with anti-inflammatory properties”, the Applicant does not note if this property is superior and/or unexpected. Applicant do not provide any evidence this property is superior and/or unexpected. The specification discloses that the stem cells differentiate into cells that express CD44 and/or Sox9, markers of chondrocytes in the presence of the septal cell exosome (Figure 2A, B). Although the specification compares septal cell exosomes to cartilage differentiation solution of undisclosed composition (page 20, paras 2-3), the specification does not provide any evidence that septal cartilage exosomes are superior in comparison to exosomes derived from other chondrocytes/cartilage tissue. Furthermore, the specification does not show that cartilage generated by exposing stem cells to exosomes, including septal cartilage exosomes, have anti-inflammatory properties. The specification actually shows that the exosomes have anti-inflammatory properties (Figure 5, 6; page 19-para 1). However, there is no evidence that this property is unexpected.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr. can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632