Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed February 3, 2026.
Amendments
Applicant's response and amendments, filed February 3, 2026, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2, 5-6, 9, 11-13, 16, 19-20, 24, 26, 29, 31-33, 36, and 40, and amended Claims 4, 8, 14, 18, 25, 30, 39, and 41-42.
Claims 1, 3-4, 7-8, 10, 14-15, 17-18, 21-23, 25, 27-28, 30, 34-35, 37-39, and 41-42 are pending.
Election/Restrictions
Applicant has elected with traverse the invention of Group III, claim(s) 1, 3-4, 7-8, 10, 14-15, 17-18, 21-23, 25, 27-28, and 30, drawn to a method of producing an enriched tissue extract.
Because applicant did not distinctly and specifically point out the supposed errors in the Group or species restriction requirement, the election has been treated as an election without traverse and the restriction and election requirement is deemed proper and therefore made final (MPEP §818).
Within Group III, Applicant has elected without traverse the following species, wherein:
i) the alternative biological sample is muscle tissue, as recited in Claim 7;
ii) the alternative tissue extract is exosomes, as recited in Claim 28;
iii) the alternative incubating step is Claim 25, step (ii);
iv) the alternative additional method step is physical stress via mechanical stress, as recited in Claim 3; and
vi) the alternative additional method step induces a stress response in the live cells, as recited in Claim 4(i).
Claims 1, 3-4, 7-8, 10, 14-15, 17-18, 21-23, 25, 27-28, 30, 34-35, 37-39, and 41-42 are pending.
Claims 10, 14, 18, 21-22, 30, 34-35, 37-39, and 41-42 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 3-4, 7-8, 15, 17, 23, 25, and 27-28 are under consideration.
Priority
This application is a 371 of PCT/US2020/072805 filed on June 8, 2022. Applicant’s claim for the benefit of a prior-filed application provisional application 63/208,766 filed on June 9, 2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed Information Disclosure Statements on May 1, 2024 and May 20, 2025 that have been considered.
The information disclosure statement filed May 1, 2024 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claim 28 is objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The multiple ‘wherein’ clauses should be separated by line indentation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
2. Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 recites the step of administering a physical stress, more specifically, a mechanical stress, to the biological sample.
Claim 4 recites wherein the physical stress induces a stress response in the live cells.
Either this is an inherent property of (that naturally flows from) the step of administering a physical stress (Claim 3), or it is not, and something of the method step of Claim 3 must change.
To the extent it is an inherent property of (that naturally flows from) the method step of Claim 3, then the instant claim fails to further limit Claim 3.
Furthermore, in regard to instant claims, it is noted that the “wherein the physical stress induces a stress response in the live cells” clause does not recite any additional structure(s) and/or method step(s), but simply states a characterization or conclusion of the results of the step of administering a physical stress, more specifically, a mechanical stress, positively recited in Claim 3. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The specification fails to disclose a step of administering a physical stress, more specifically, a mechanical stress that does NOT also induces a stress response in the live cells”. 'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
3. Claim(s) 4 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.
Claim 3 recites the step of administering a physical stress, more specifically, a mechanical stress, to the biological sample.
Claim 4 recites wherein the physical stress induces a stress response in the live cells.
Either this is an inherent property of (that naturally flows from) the step of administering a physical stress (Claim 3), or it is not, and something of the method step of Claim 3 must change.
The claim denotes that not all of the steps of administering a physical stress, including, more specifically, a mechanical stress, are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the method step of Claim 3, then something of the method step of Claim 3 must change. Claim 4 is considered to lack adequate written description for failing to recite the additional structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language “induces a stress response in the live cells”.
The limitation “wherein the physical stress induces a stress response in the live cells” clause does not recite any additional structure(s) and/or method step(s), but simply states a characterization or conclusion of the results of the step of administering a physical stress, more specifically, a mechanical stress, positively recited in Claim 3.
The functional characteristic does not follow from (is not an inherent property of) the method step recited in Claim 3.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The specification fails to disclose a step of administering a physical stress, more specifically, a mechanical stress that does NOT also induces a stress response in the live cells”.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
4. Claim 8 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.
The term “substantially” in Claim 8 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
5. Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites the step of providing a biological sample comprising live cells.
Claim 7 recites wherein the biological sample comprises tissue or isolated cells from muscle.
Claim 8 recites wherein the biological sample comprises:
i) a single type of tissue and is substantially free of other types of tissue; or
ii) a portion of tissue or a plurality of tissue pieces.
Claim 8 is considered to not further limit Claim 7 because it is natural law of anatomy and cell biology that the step providing a biological sample comprising live cells, including muscle tissue or isolated muscle cells will necessarily yield:
i) a single type of tissue and is substantially free of other types of tissue; or
ii) a portion of tissue or a plurality of tissue pieces.
To put it another way, mere recitation of each isolated cell/tissue composition possibilities (Claim 8) that are naturally achieved per Claims 1 and 7 fails to further limit Claims 1 and 7.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
6. Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 recites the step of providing a biological sample comprising live cells.
Claim 15 recites wherein the biological sample is from a deceased donor subject or a living donor subject.
Claim 15 is considered to not further limit Claim 7 because it is natural law of biology that there are only two states of reality from which the biological sample comprising living cells is obtained, to wit: a living or dead donor subject. Mere recitation of both states of reality fails to further limit the independent claim. Even with in vitro cultured cell lines, those of ordinary skill in the art have long-recognized that the cells were originally obtained from either a living or dead donor subject.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 (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 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.
7. Claim(s) 1, 3-4, 7-8, 15, 17, 23, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zanotti et al (Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis, Matrix Biology 74: 77-100, 2018).
With respect to Claim 1, Zanotti et al is considered relevant prior art for having taught a method of producing an enriched tissue extract, the method comprising the step(s) of:
(a) providing a biological sample comprising live cells (e.g. Abstract, “muscle-derived fibroblasts of DMD patients”;
(b) incubating the biological sample in an extraction solution for a period of time sufficient for biologically active components to be extracted from the biological sample thereby forming an enriched tissue extract (e.g. pg 93, col.2, Methods, Exosome isolation); and
(c) separating the enriched tissue extract from the processed biological sample (e.g. pg 93, col.2, Methods, Exosome isolation).
With respect to Claims 15 and 17, Zanotti et al taught wherein the biological sample is from a living donor subject, to wit, a human donor subject (e.g. pg 93, col. 2, Methods, Human muscle cell cultures, “muscle biopsies”).
With respect to Claims 7-8, Zanotti et al taught wherein the biological sample comprises tissue or isolated cells from muscle, wherein the biological sample comprises a single type of tissue and is substantially free of other types of tissue (e.g. pg 93, col.2, Methods, Human muscle cell cultures, “purity of…”).
With respect to Claim 28, Zanotti et al taught wherein the enriched tissue extract comprises one or more of exosomes (e.g. pg 93, col.2, Methods, Exosome isolation).
With respect to Claim 23, Zanotti et al taught wherein the extraction solution comprises a cell culture medium comprising serum and a buffered solution (which necessarily comprises a salt) (e.g. pgs 93-94, joining para, Methods, Exosome isolation, Total Exosome Isolation kit).
With respect to Claim 27, Zanotti et al taught wherein the separating step comprises separating the enriched tissue extract from the biological sample using at least centrifugation (e.g. pgs 93-94, joining para, Methods, Exosome isolation, Total Exosome Isolation kit).
With respect to Claim 3, Zanotti et al taught wherein a step of administering a physical stress to the biological sample occurs prior to incubation in step (b),
wherein the physical stress comprises a mechanical stress (e.g. pg 93, col. 2, Methods, Human muscle cell cultures, “immunomagnetic selection”, “early [cell culture] passages”).
With respect to Claim 4, as discussed above, such is considered to not further limit Claim 3. See above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, rejection.
To the extent Applicant argues otherwise, see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
The specification fails to disclose a step of administering a physical stress, more specifically, a mechanical stress that does NOT also induces a stress response in the live cells”.
It is considered natural law of cell biology that the mechanical stress placed on the cells via the method steps of performing immunomagnetic selection and/or cell culture passaging steps would necessarily “induce a stress response in the live cells”, absent objective evidence to the contrary.
Thus, Zanotti et al anticipate the claims.
8. Claim(s) 1, 3-4, 7-8, 15, 17, 23, 25, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al (Cyclic Stretch Force Induces Periodontal Ligament Cells to Secrete Exosomes That Suppress IL-1beta Production Through the Inhibition of the NF-kB Signaling Pathway in Macrophages, Frontiers in Immunology 10: e1310, 17 pages, doi.10.3389/fimmu.2019.01310; available online June 20, 2019).
With respect to Claims 1 and 25, Wang et al is considered relevant prior art for having taught a method of producing exosomes from ligament cells, the method comprising the step of incubating the cells in an extraction solution, e.g. culture medium, wherein the incubating step further comprises agitating the cells (e.g. Abstract, “We examined the secretion of exosomes from… cells stimulated with cyclic stretch (syn. agitation)”).
With respect to Claims 15 and 17, Wang et al taught wherein the biological sample is from a living donor subject (e.g. pg 2, col. 2, Methods, Cell lines), including a human donor subject (e.g. pg 3, col. 1, Methods, Primary cells, “human… obtained from clinically healthy patients”).
With respect to Claims 7-8, Wang et al taught wherein the biological sample comprises tissue or isolated ligament cells, wherein the biological sample comprises a single type of isolated cells and is substantially free of other types of tissue (e.g. pg 2, col. 2, Methods, Cell lines; pg 3, col. 1, Methods, Primary cells, “human… obtained from clinically healthy patients”).
With respect to Claim 28, Wang et al taught wherein the enriched tissue extract comprises one or more of exosomes (e.g. pg 3, col.2, Methods, Exosome isolation).
With respect to Claim 23, Wang et al taught wherein the extraction solution comprises a cell culture medium comprising serum and a buffered solution (which necessarily comprises a salt) (e.g. pg 3, col. 2, Methods, Cyclic Stretch).
With respect to Claim 27, Wang et al taught wherein the separating step comprises separating the enriched tissue extract from the biological sample using at least centrifugation (e.g. pg 3, col. 2, Methods, Cyclic Stretch, “prepared by centrifugation”; Isolation of Exosomes, “centrifugation”).
With respect to Claim 3, Wang et al taught wherein a step of administering a physical stress to the biological sample occurs prior to incubation in step (b),
wherein the physical stress comprises a mechanical stress (e.g. pg 3, col. 2, Methods, Primary cells, “minced”, “subculture”; pg 3, col. 2, Methods, Cyclic Stretch, “seeded”).
With respect to Claim 4, as discussed above, such is considered to not further limit Claim 3. See above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, rejection.
To the extent Applicant argues otherwise, see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
The specification fails to disclose a step of administering a physical stress, more specifically, a mechanical stress that does NOT also induces a stress response in the live cells”.
It is considered natural law of cell biology that the mechanical stress placed on the cells via the method steps of performing immunomagnetic selection and/or cell culture passaging steps would necessarily “induce a stress response in the live cells”, absent objective evidence to the contrary.
Thus, Wang et al anticipate the claims.
9. Claim(s) 1, 3-4, 7-8, 15, 17, 23, 25, and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guo et al (Stimulating Extracellular Vesicles Production from Engineered Tissues by Mechanical Forces, Nano Letters 21: 2497-2504, available online March 12, 2021).
With respect to Claims 1 and 25, Guo et al is considered relevant prior art for having taught a method of producing exosomes from muscle cells, the method comprising the step of incubating the cells in an extraction solution, e.g. culture medium, wherein the incubating step further comprises agitating the cells (e.g. Abstract, “applying mechanical stimuli, including flow and stretching (syn. agitation)”).
Guo et al taught that current extracellular vesicle production from cells relies heavily on 2D cell culture, which is not only less physiologically relevant to cells, but also requires substantial culture medium and space. However, by applying mechanical forces, including agitation, extracellular vesicle production is significantly enhanced (e.g. Abstract).
With respect to Claims 15 and 17, Guo et al taught wherein the biological sample comprises tissue or isolated cells, wherein the biological sample comprises a single type of isolated cells and is substantially free of other types of tissue (e.g. pg 2501, col. 1, Methods, Cell culture “primary human skeletal muscle cells”).
With respect to Claims 7-8, Guo et al taught wherein the biological sample comprises tissue or isolated cells, wherein the biological sample comprises a single type of isolated cells and is substantially free of other types of tissue (e.g. pg 2501, col. 1, Methods, Cell culture “primary human skeletal muscle cells”).
With respect to Claim 28, Guo et al taught wherein the enriched tissue extract comprises one or more of exosomes (e.g. 2497, col. 1, “extracellular vesicles (EVs), including exosomes”).
With respect to Claim 23, Guo et al taught wherein the extraction solution comprises a cell culture medium comprising serum and a buffered solution (which necessarily comprises a salt) (e.g. pg 2502, col. 1, Methods, Cell Seeding, “growth medium”).
With respect to Claim 27, Guo et al taught wherein the separating step comprises separating the enriched tissue extract from the biological sample using at least centrifugation (e.g. pg 2502, col. 1, Methods, EV isolation, “performed using differential centrifugation”, “ultracentrifuged”).
With respect to Claim 3, Guo et al taught wherein a step of administering a physical stress to the biological sample occurs prior to incubation in step (b),
wherein the physical stress comprises a mechanical stress (e.g. pg 2502, col. 1, Methods, Cell Seeding, “trypsinization”, “suspended”, “seeded”).
With respect to Claim 4, as discussed above, such is considered to not further limit Claim 3. See above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, rejection.
To the extent Applicant argues otherwise, see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
The specification fails to disclose a step of administering a physical stress, more specifically, a mechanical stress that does NOT also induces a stress response in the live cells”.
It is considered natural law of cell biology that the mechanical stress placed on the cells via the method steps of performing immunomagnetic selection and/or cell culture passaging steps would necessarily “induce a stress response in the live cells”, absent objective evidence to the contrary.
Thus, Guo et al anticipate the claims.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
10. Claim(s) 1, 3-4, 7-8, 15, 17, 23, 25, and 28 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Zanotti et al (2018; of record), as applied to Claims 1, 3-4, 7-8, 15, 17, 23, and 28 above, and in further view of Wang et al (available online June 20, 2019; of record) and Guo et al (available online March 12, 2021; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Zanotti et al is considered relevant prior art for having taught a method of producing an enriched tissue extract, the method comprising the step(s) of:
(a) providing a biological sample comprising live cells (e.g. Abstract, “muscle-derived fibroblasts of DMD patients”;
(b) incubating the biological sample in an extraction solution for a period of time sufficient for biologically active components to be extracted from the biological sample thereby forming an enriched tissue extract (e.g. pg 93, col.2, Methods, Exosome isolation); and
(c) separating the enriched tissue extract from the processed biological sample (e.g. pg 93, col.2, Methods, Exosome isolation).
Zanotti et al do not teach wherein the incubating step comprises agitating the sample in an extraction solution.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 25, Wang et al is considered relevant prior art for having taught a method of producing exosomes from ligament cells, the method comprising the step of incubating the cells in an extraction solution, e.g. culture medium, wherein the incubating step further comprises agitating the cells (e.g. Abstract, “We examined the secretion of exosomes from… cells stimulated with cyclic stretch (syn. agitation)”).
Similarly, Guo et al is considered relevant prior art for having taught a method of producing exosomes from muscle cells, the method comprising the step of incubating the cells in an extraction solution, e.g. culture medium, wherein the incubating step further comprises agitating the cells (e.g. Abstract, “applying mechanical stimuli, including flow and stretching (syn. agitation)”).
Guo et al taught that current extracellular vesicle production from cells relies heavily on 2D cell culture, which is not only less physiologically relevant to cells, but also requires substantial culture medium and space. However, by applying mechanical forces, including agitation, extracellular vesicle production is significantly enhanced (e.g. Abstract).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in cell biology and cell culture methods. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the method of producing exosomes from a biological sample of cells, e.g. muscle cells, to comprise the step of agitating the cells during the incubation step with motivation and a reasonable expectation of success because those of ordinary skill in the art previously recognized and successfully reduced to practice:
i) culturing the artisan’s cell type of interest, including muscle cells, in a culture medium under conditions of agitation, e.g. cyclic stretch and/or mechanical stimulation, to produce extracellular vesicles, including exosomes (Wang et al, Guo et al); and
ii) current extracellular vesicle production from cells relies heavily on 2D cell culture, which is not only less physiologically relevant to cells, but also requires substantial culture medium and space; however, by applying mechanical forces, including agitation, extracellular vesicle production is significantly enhanced (Guo et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 15 and 17, Zanotti et al taught wherein the biological sample is from a living donor subject, to wit, a human donor subject (e.g. pg 93, col. 2, Methods, Human muscle cell cultures, “muscle biopsies”).
Wang et al taught wherein the biological sample is from a living donor subject (e.g. pg 2, col. 2, Methods, Cell lines), including a human donor subject (e.g. pg 3, col. 1, Methods, Primary cells, “human… obtained from clinically healthy patients”).
Guo et al taught wherein the biological sample comprises tissue or isolated cells, wherein the biological sample comprises a single type of isolated cells and is substantially free of other types of tissue (e.g. pg 2501, col. 1, Methods, Cell culture “primary human skeletal muscle cells”).
With respect to Claims 7-8, Zanotti et al taught wherein the biological sample comprises tissue or isolated cells from muscle, wherein the biological sample comprises a single type of tissue and is substantially free of other types of tissue (e.g. pg 93, col.2, Methods, Human muscle cell cultures, “purity of…”).
Wang et al taught wherein the biological sample comprises tissue or isolated cells, wherein the biological sample comprises a single type of isolated cells and is substantially free of other types of tissue (e.g. pg 2, col. 2, Methods, Cell lines; pg 3, col. 1, Methods, Primary cells, “human… obtained from clinically healthy patients”).
Guo et al taught wherein the biological sample comprises tissue or isolated cells, wherein the biological sample comprises a single type of isolated cells and is substantially free of other types of tissue (e.g. pg 2501, col. 1, Methods, Cell culture “primary human skeletal muscle cells”).
With respect to Claim 28, Zanotti et al taught wherein the enriched tissue extract comprises one or more of exosomes (e.g. pg 93, col.2, Methods, Exosome isolation).
Wang et al taught wherein the enriched tissue extract comprises one or more of exosomes (e.g. pg 3, col.2, Methods, Exosome isolation).
Guo et al taught wherein the enriched tissue extract comprises one or more of exosomes (e.g. 2497, col. 1, “extracellular vesicles (EVs), including exosomes”).
With respect to Claim 23, Zanotti et al taught wherein the extraction solution comprises a cell culture medium comprising serum and a buffered solution (which necessarily comprises a salt) (e.g. pgs 93-94, joining para, Methods, Exosome isolation, Total Exosome Isolation kit).
Wang et al taught wherein the extraction solution comprises a cell culture medium comprising serum and a buffered solution (which necessarily comprises a salt) (e.g. pg 3, col. 2, Methods, Cyclic Stretch).
Guo et al taught wherein the extraction solution comprises a cell culture medium comprising serum and a buffered solution (which necessarily comprises a salt) (e.g. pg 2502, col. 1, Methods, Cell Seeding, “growth medium”).
With respect to Claim 27, Zanotti et al taught wherein the separating step comprises separating the enriched tissue extract from the biological sample using at least centrifugation (e.g. pgs 93-94, joining para, Methods, Exosome isolation, Total Exosome Isolation kit).
Wang et al taught wherein the separating step comprises separating the enriched tissue extract from the biological sample using at least centrifugation (e.g. pg 3, col. 2, Methods, Cyclic Stretch, “prepared by centrifugation”; Isolation of Exosomes, “centrifugation”).
Guo et al taught wherein the separating step comprises separating the enriched tissue extract from the biological sample using at least centrifugation (e.g. pg 2502, col. 1, Methods, EV isolation, “performed using differential centrifugation”, “ultracentrifuged”).
With respect to Claim 3, Zanotti et al taught wherein a step of administering a physical stress to the biological sample occurs prior to incubation in step (b),
wherein the physical stress comprises a mechanical stress (e.g. pg 93, col. 2, Methods, Human muscle cell cultures, “immunomagnetic selection”, “early [cell culture] passages”).
Wang et al taught wherein a step of administering a physical stress to the biological sample occurs prior to incubation in step (b),
wherein the physical stress comprises a mechanical stress (e.g. pg 3, col. 2, Methods, Primary cells, “minced”, “subculture”; pg 3, col. 2, Methods, Cyclic Stretch, “seeded”).
Guo et al taught wherein a step of administering a physical stress to the biological sample occurs prior to incubation in step (b),
wherein the physical stress comprises a mechanical stress (e.g. pg 2502, col. 1, Methods, Cell Seeding, “trypsinization”, “suspended”, “seeded”).
With respect to Claim 4, as discussed above, such is considered to not further limit Claim 3. See above 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, rejection.
To the extent Applicant argues otherwise, see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
The specification fails to disclose a step of administering a physical stress, more specifically, a mechanical stress that does NOT also induces a stress response in the live cells”.
It is considered natural law of cell biology that the mechanical stress placed on the cells via the method steps of performing immunomagnetic selection and/or cell culture passaging steps would necessarily “induce a stress response in the live cells”, absent objective evidence to the contrary.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
11. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638