DETAILED ACTION
Claims 1-10, 18-22, 27-28 and 30 from the claim set filed October 21, 2022 are pending. Claims 8-9 (non-elected species), 18-22 (non-elected Group II), 27-28 (non-elected Group III) and 30 (non-elected species) are withdrawn. Claims 1-7 and 10 are being examined on the merits herein.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10 and 30, drawn to a treatment, in the reply filed May 5, 2025 is acknowledged. Examiner further acknowledges the election of species (a) for a cell type, claims 2-10, and species (a) for a method, claims 6 and 7. Thus, claims 8-9, 18-22, 27-28 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-7 and 10 will be examined on the merits herein.
Priority
A claim for benefit of a prior-filed application under 35 U.S.C. 119(a)-(f) or under 35
U.S.C. 120, 121, 365(a)-(c), 386 (a) or 386(c) has been made. The effective filing date of the
present application is October 2, 2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 3/17/2022, 5/12/2022, 7/10/2024, 11/18/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because the character of the letters is poor in many of the figures. Examiner notes the character of the letters is especially poor in Figures 1, 5, 6, and 12.
See 37 CFR 1.84(l)
The drawings are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)). The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.” Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation “FIG.” must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claims 1-7 and 10 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
In regards to claim 1, the metes and bounds of the claim cannot be determined with the language of the claim as currently written. The issue at hand is the use of the term “providing”. The term “providing” is not defined by the claims, 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.
Claim 1, as currently written, does not require an active step of administering. I.e., an active step of administering has not been detailed. The term “providing” reads upon handing the cells to a subject. Thus, when looking at the dependent claims, how is a tissue being repaired through “providing” (i.e., possibly just handing) a subject the cells of claim 1. As an active step of administering has not been detailed within claim 1, the claim is thus indefinite. It is unclear what “providing” entails.
Dependent claims 2-7 and 10 are rejected based upon their dependency to claim 1 and for not remedying the issue at hand.
Claim 1 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
In regards to claim 1, it is unclear what (“TIMP-1 secretion high”) and (“MMP13 gene expression low”) is meant to entail. As the claim requires TIMP-1 secretion + and MMP13 gene expression -, it is unclear if the use of the parentheses and quotes of the following phrases, i.e., (“TIMP-1 secretion high”) and (“MMP13 gene expression low”), is meant to be a further limitation on the claim. What are the parameters on these phrases? Is Applicant trying to further define TIMP-1 secretion + and MMP13 gene expression -? Thus, the metes and bounds of the claim cannot be determined and the claim is indefinite.
Dependent claims 2-7 and 10 are rejected based upon their dependency to claim 1 and for not remedying the issue at hand.
Claim 2 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
In regards to claim 2, the metes and bounds of the claim cannot be determined with the language of the claim as currently written. The issue at hand is the use of the term “substantially”. The term “substantially” is not defined by the claims, 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. Thus, a POSITA would not be apprised as to what “substantially” no multipotent potential entails. The claim is thus indefinite.
Claim 6 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
In regards to claim 6, the phrase “such as” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention or are optional. (I.e., "such as torn meniscus" and “such as torn ligament”.) See MPEP § 2173.05(d). Examiner reads “such as” as optional.
Claim Rejections - 35 USC § 102
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.
Claims 1, 2, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chapman (Chapman et al., Stem Cells International (2017) (2905104; IDS filed 3/17/2022) as evidenced by Ghaneialvar (Ghaneialvar et al., Ind J Clin Biochem (2018) 33(1): 46-52; PTO 892).
In regards to claim 1, Chapman teaches of the therapeutic benefit for late, but not early, passage MSCs on pain behavior in an animal model of osteoarthritis (OA) (Title). Chapman teaches the use of passage 10 (P10) murine bone marrow derived MSCs (p2, 2.4). Chapman teaches of intra-articular injection of late passage MSCs (P10) (p3, 2.6.1) and the effect of said injection on pain behavior (p4, 2nd column, 1st paragraph). Chapman teaches the passage number of MSCs markedly influences the effects of these cells on pain behavior following their injection into the knee joint in a surgical model of OA pain. Chapman teaches late passage MSCs significantly reduced weight-bearing difference, a surrogate index of pain on loading, whereas early passage MSCs exacerbated weight-bearing difference postinjection (p5, Discussion). Chapman teaches that higher passage cells may have an increased potential for therapeutic application (p9, 1st column, 1st paragraph). Thus, Chapman teaches a method of treatment comprising providing a therapeutically effective amount of cells.
Chapman does not teach per se of cells that are CD90+, CD105+ and CD45-. However, as is evidenced by Ghaneialvar, human and mouse MSCs express CD105 and CD90 and are negative for CD45 (Abstract). Thus, it is inherent that the murine MSCs of Chapman are CD90+, CD105+ and CD45-.
Chapman does not per se teach of TIMP-1 secretion+ and MMP13 gene expression-.
The instant application teaches that in usual culture conditions (p28, Results 1st paragraph; p37 Isolation and expansion of human marrow derived MSCs for in vitro studies) MSCs keep their TIMP-1 high expression over many passages (Fig 7C) but gradually lose their MMP13 expression (Fig 7A-B). Specifically, the instant application teaches the MMP13 gene is a marker of early passage cells which is lost with ageing of MSCs in vitro and further teaches secretion of the TIMP-1 protein is a marker of MSCs that is independent of in vitro ageing (Fig 7, p6). The instant application teaches MMP13 data from transcriptomics analysis shows decreasing gene expression with increasing passage number, with low MMP13 gene expression by passage 5 (Fig 7A-B). Additionally, the instant application teaches TIMP-1 data from proteomics analysis shows continuous protein secretion with increasing passage number (Fig 7C-D). The instant application further teaches a population of cells of the invention may comprise cells that have been subject to at least 5 passages (i.e., the cells will have low MMP13 gene expression and high TIMP-1 secretion) (p16, cell culture).
Importantly, the authors did not purify the cell population but simply analyzed the expression profile of the cell populations at different time points (p37 last paragraph-p38 first paragraph). Since these changes are inherent to any MSC population that is passaged several times, the MSC population disclosed by Chapman will also be “enriched” in cells expressing high TIMP-1 levels and low MMP13 levels compared to a fresh MSC population.
Thus, Chapman teaches of the cell population of claim 1, i.e., Chapman teaches of cells that are CD90+; CD105+; CD45-; TIMP-1 secretion + (i.e., TIMP-1 secretion high); and MMP13 gene expression- (i.e., MMP13 gene expression low).
Thus, the claim is anticipated and is properly rejected.
In regards to claim 2, Chapman teaches the method of claim 1. Further, Examiner notes the limitation “wherein the cells have substantially no multipotent potential” is a wherein statement that is directed to an intended result. It is noted that as indicated in MPEP § 2111.04, a wherein clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.
As discussed above in regards to claim 1, Chapman teaches the same cells that are required by the limitations of claim 1. As discussed supra, it is inherent that the cells of Chapman express the same cell surface markers and have the same TIMP-1 secretion and MMP13 gene expression as required by the limitations of claim 1. As no other steps have been provided in the method of claim 1 in regards to said cells, it is thus inherent that the cells of Chapman and the instant application are one and the same. Thus, because the cells are one and the same, it therefore stands to reason that said cells would inherently have substantially no multipotency potential.
Under the principles of inherency, if a prior art method, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art method. When the prior art method is the same as a method described in the specification for carrying out the claimed method, it can be assumed the method will inherently perform the claimed process and produce the identical or substantially identical product. See In re Best, 562 F. 2d, 1252, 1255, 195 USPQ 430, 433 (CCPA 1977) and Ex parte Novitski, 26 USPQ 2d 1389 (Bd. Pat. App. & inter. 1993). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of the invention, but only that the subject matter is in fact inherent in the prior art reference. See Schering Corp. v. Geneva Pharm. Inc, 339 F.3d 1373, 1377, 67, USPQ2d 1664, 1668 (Fed. Cir. 2003). See also Toro Co. v. Deere & Co. 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004). MPEP 2112.01
Therefore, the claim is anticipated and is properly rejected.
In regards to claim 10, Chapman teaches the method of claim 1. As no other steps have been provided in the method of claim 1 in regards to said cells and the manner in which they are cultured, treated, etc., it is thus inherent that the cells of Chapman and the instant application are one and the same. Thus, because the cells and the method of Chapman are one and the same as the instant application, it therefore stands to reason that said cells would inherently comprise a population comprising at least 15% of said cells.
Under the principles of inherency, if a prior art method, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art method. When the prior art method is the same as a method described in the specification for carrying out the claimed method, it can be assumed the method will inherently perform the claimed process and produce the identical or substantially identical product. See In re Best, 562 F. 2d, 1252, 1255, 195 USPQ 430, 433 (CCPA 1977) and Ex parte Novitski, 26 USPQ 2d 1389 (Bd. Pat. App. & inter. 1993). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of the invention, but only that the subject matter is in fact inherent in the prior art reference. See Schering Corp. v. Geneva Pharm. Inc, 339 F.3d 1373, 1377, 67, USPQ2d 1664, 1668 (Fed. Cir. 2003). See also Toro Co. v. Deere & Co. 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004). MPEP 2112.01
Therefore, the claim is anticipated and is properly rejected.
Claim Rejections - 35 USC § 103
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.
Claims 3-7 are rejected under 35 U.S.C. 103 as being unpatentable over Chapman, as evidenced by Ghaneialvar, in view of Estes (Estes, et al., Journal of Cellular Physiology (2006) 209:987-995; PTO 892) as evidenced by Tsuji (Tsuji, et al., World J Stem Cells (2014) 6(3): 312-321; PTO 892) and Bacenkova (Bacenkova, et al., International Journal of Molecular Sciences (2023) 23 (17096); PTO 892). Claim 7 is rejected under 35 USC 103 as being unpatentable over Chapman, as evidenced by Ghaneialvar, in view of Estes as evidenced by Tsuji and Bacenkova, and as further evidenced by Wang (Wang et al., Journal of Orthopedic Research (2013); IDS filed 3/17/2022).
In regards to claim 3, Chapman teaches the method of claim 1. While Chapman teaches a method of treating pain in an animal model of osteoarthritis, Chapman does not teach a method for the promotion of tissue repair.
Examiner acknowledges Chapman examined the effects of late versus early passage MSCs not only on pain behavior but also on structural changes to the knee joint (i.e., tissue repair) and circulating levels of tumor necrosis factor alpha and interleukin 10 (i.e., inflammation) in a surgical model of OA in the rat (p2, 2nd paragraph, 1st column). Chapman teaches late passage MSCs did not alter structural damage or synovial inflammation (p6, 1st column) and summarizes that the progression of MNX-induced joint pathology was not halted by intra-articular injection of late passage MSCs, suggesting that at least in this model the effects of MSC treatment on pain behavior are not associated with increased joint repair (p6, 2nd column).
However, Chapman further notes, there is evidence of other phenotypic shifts in MSCs with prolonged culture which may provide insight. Chapman teaches earlier studies examining passage-dependent differences to chondrogenic potential (i.e., tissue repair potential) of MSCs have produced varied results with some studies reporting a maintenance of the chondrogenic potential of the cells up to passage 20 or increase in COL2A1 and AGC1 expression from P4 to P9 in human adipose derived adult stem cells. Another study reported a reduction of chondrogenic capabilities of MSCs at late passage. With an increasing passage number, MSCs isolated from synovium shows migratory behavior similar to chondrocytes, whilst at low passage, a reduced ability to undergo chondrogenesis was observed.
Chapman summarizes the varied results in regards to phenotypic shifts of late passaged MSCs by stating, “What is clear is that selection of populations of cells for therapy will depend on the level of preculture with significant changes in phenotype and potential therapeutic activity as a result of prolonged culture.” (p9, 1st column, 1st full paragraph). I.e., when determining MSCs to be used for therapy, one must look at the source of the cells, how the cells were cultured, how long the cells were cultured, etc., as each variable can cause a change in phenotype, especially in regards to repair and immunomodulation.
Thus, Chapman teaches a method of treating pain in an animal model of osteoarthritis while noting more research is needed in regards to late passage MSCs and their effects on osteoarthritis, i.e., joint regeneration (i.e., tissue repair) and inflammation, as osteoarthritis involves not only pain management but structural changes and immunomodulation.
Estes teaches extended passaging increases the chondrogenic potential of human adipose derived adult stem cells h(ADAS) (Title). As a POSITA will appreciate, and as is evidenced by Tsuji, adipose derived stem cells are MSCs (Abstract). Tsuji additionally teaches adipose derived stem cells (i.e., MSCs) express the typical mesenchymal markers such as CD90+, CD105+ and CD45- (p313, 2nd column, last paragraph).
Estes does not per se teach of TIMP-1 secretion and MMP13 gene expression, but as discussed supra in regards to claim 1, it is inherent Estes teaches of cells that are CD90+; CD105+; CD45-; TIMP-1 secretion + (i.e., TIMP-1 secretion high); and MMP13 gene expression- (i.e., MMP13 gene expression low) as Estes teaches the use of passage 9 cells (p988, 2nd column, 1st full paragraph).
As a POSITA will appreciate, and as is evidenced by Bacenkova, osteoarthritis (OA) is a very common joint disease that begins with the degeneration of joint cartilage and in the case of pathological processes, the production of collagen by chondrocytes changes (4.1). Chondrocytes are a differentiated cell type in a resting state that ensure the maintenance of the physiological state of the ECM of the articular cartilage. Chondrocyte dedifferentiation in an organism causes degeneration and is associated with OA, i.e., which is associated with cartilage damage (5.2). Thus, the teachings of Estes, i.e., that extended passaging increases the chondrogenic potential of hADAS, would motivate a POSITA to combine the teachings of Estes and Chapman in order to have a method of treating tissue regeneration (i.e., tissue repair) in osteoarthritis.
Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the late passage MSCs taught by Chapman for the late passage adipose derived MSCs taught by Estes in order to have a method of treating osteoarthritis in regards to tissue repair.
The skilled artisan would have had a reasonable expectation of successfully substituting the cells of Chapman for the cells of Estes for treating osteoarthritis. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the claim is obvious and is properly rejected.
In regards to claims 4 and 5, Chapman teaches the method of claim 1. Further, and as discussed supra, Estes and Chapman teach a method for the treatment of cartilage.
Thus, the claims are obvious and are properly rejected.
In regards to claim 6, the above cited references teach the method of claim 3. Further and as discussed supra, Chapman teaches a method of treating osteoarthritis.
Thus, the claim is obvious and is properly rejected.
In regards to claim 7, the above cited references teach the method of claim 3. Further and as discussed supra, Chapman and Estes teach a method for the promotion of tissue repair. As both Chapman and Estes teach the cells required by claim 1, i.e., cells that are CD90+; CD105+; CD45-; TIMP-1 secretion + (i.e., TIMP-1 secretion high); and MMP13 gene expression- (i.e., MMP13 gene expression low), it is inherent that said cells would promote tissue repair through the stimulation of trophic repair.
Further, and as is evidenced by Wang, late passage MSCs (i.e., the cells required by claim 1 and taught by Chapman and Estes) are known to cause trophic stimulation of articular chondrocytes (Title).
Thus, it is inherent the cells of Chapman and Estes promote tissue repair by the stimulation of trophic repair.
Thus, the claim is obvious and is properly rejected.
Prior Art Not Applied
Yang (Yang et al., Stem Cell Research (2018) 9(131: 1-14; IDS filed 3/17/2022)
Yang teaches the cells required of claim 1. The paper of Yang details the changes in phenotype and differentiation potential of hMSCs aging in vitro. Yang teaches through passage 8 and discusses the cell morphology, proliferative capacity, and surface marker expression at the end of each passage. Yang further teaches of the adipogenic and osteogenic differentiation capability of said cells at early passage (P4) and late passage (P8). Yang further discusses said cells hold great promise for regenerative medicine.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE R SMALL whose telephone number is (703)756-4783. The examiner can normally be reached Monday - Friday 8:30am-4pm.
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, Chris Babic can be reached on 571-272-8507. 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.
/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633