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 .
Response to Amendment
Claims 2-5, 9-13, 15-16, 18, 20, and 24-29 have been cancelled. Claims 1, 6-8, 14, 17, 21-23 have been amended, and Claims 31-32 have been newly added as requested in the amendment filed on 13 October 2022. Following the amendment, claims 1, 6-8, 14, 17, 19, 21-23, and 30-32 are pending in the instant application.
Claims 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions.
Claims 1, 6-8, 14, 17, 19, 21, and 30-32 are under examination in the instant office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6-8, 14, 17, 19, 21, and 30-32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the terms “deteriorated”; “increased” and “reduced” in parts (b), (c), (e), and (g) through (i); “increases”; “enhance”; and “balanced”. All of these are relative terms which render the claim indefinite. Similarly, Claim 7 recites reduced signaling, phosphorylation, , expression, etc. but there are no active steps recites whereby these reductions are assessed. While the claims expressly state some of these relativities are “compared to an untreated control”, “compared to a non-antibody treated control”, or compared to BMECs obtained from a control subject, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention because it is unclear whether or not direct infringement of the method requires assessing these states, since there are no active method steps. For example, it is unclear if assessing the HSC niche for increased vascular permeability (Claim 1, part ii) comprising, i.e. increased HSC apoptosis (Claim 1, part e) and i.e. reduced inflammation (wherein clause after part i) are all required for infringement of the method. Or, is the sole active method step required for infringement: administering a pharmaceutical composition alone or in combination with a stem cell co-therapy comprising transplanting a therapeutic amount of multipotent, self-renewing HSCs, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a thrombospondin 1 (TSP1) inhibitor, wherein the TSP1 inhibitor is either neutralizing anti-thrombospondin-1 mouse monoclonal antibody clone A4.1 (Thermofisher Scientific, Cat. No. MA5-13377) that reduces the biological activity of TSP1, or an siRNA targeting TSP1, wherein the siRNA targeting TSP1 comprises a sense strand comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and an antisense strand comprising the sequence of SEQ ID NO: 2 or SEQ ID NO: 4. Absent method steps for assessing these effects, then for purposes of applying prior art, the claims will be interpreted as requiring: administering, alone or in combination with a stem cell co-therapy, a neutralizing anti-thrombospondin-1 mouse monoclonal antibody clone A4.1 (Thermofisher Scientific, Cat. No. MA5-13377), or an siRNA targeting TSP1comprising a sense strand comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and an antisense strand comprising the sequence of SEQ ID NO: 2 or SEQ ID NO: 4. This rejection affects the scope of all depending claims.
Claim 6 is indefinite wherein it recites the method of claim 1, “wherein the HSC niche comprises hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), resident niche cells comprising osteoblastic cells that regulate stem cell pool size during hematopoiesis, and secreted and membrane bound factors comprising chemokines”. These limitations add no material or methodological limitation upon the scope of the parent claim. Rather, this recitation merely states the cell types and factors that are inherent within the HSC niche, of the parent claim, and their inherent function “regulate stem cell pool size”. MPEP section 2173.05(g) that states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states the following factors determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. It is unclear how the recitation of claim 6 imposes a difference in scope over the parent claim. Since the claim fails to meet all three criteria set forth in MPEP 2173.05(g), then the claim is rejected as being indefinite.
Claim 7 is similarly indefinite wherein it recites the microniche within the bone marrow hematopoietic microenvironment of the HSC niche containing BMECs includes one or more of (i) through (v). As stated above, there are no active method steps whereby the conditions of (i) through (v) are assessed. Thus, it is unclear if these effects are required or not for direct infringement of the method of the invention.
Similarly, Claim 8 is indefinite wherein it recites “reduced” signaling that causes: (a) a functional defect in HSCs including: “increase” in total hematopoietic cell; frequency of phenotype; a significant myeloid bias; “reduced” activity, polarization capacity; an “increase” in double strand DNA breaks, etc.; or (b) wherein expression levels are upregulated in BMECs from the subject compared to control subjects. First, the relativity of the terms within part (a) are not resolved by either the claim itself or the specification. In other words, the terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree. While part (b) of the claim resolves this issue by stating “compared to …control subjects”, what is missing from the claim as a whole are active method steps for assessing any of the claimed increases/decreases. Thus, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention and whether or not these effects are required for infringement.
Claim 14, recites the limitation "the myelosuppressive insult" in Claim 1. There is insufficient antecedent basis for this limitation in the parent claim.
Claim 17 is indefinite wherein it further limits the effects that are recited within Claim 1. For example, claim 17 states, “wherein the increased myeloid-biased differentiation … is at the expense of lymphopoiesis”; “wherein the loss of quiescence …leads to a transient increase in HSCs”; or, hematopoietic defects in the HSC niche of the bone marrow … microenvironment include changes in HSC gene expression.” First, it is unclear if claim 1 even requires assessment of, for example, “increased myeloid-biased differentiation of HSCs”, “loss of quiescence”, etc. Secondly, it is entirely unclear whether or not infringement of Claim 17 further requires assessing, for example, lymphopoiesis or gene expression. Again, this claim appears to recite intended results/effects without imposing any method steps over the active steps recited in the parent claim.
Claim 19 is indefinite wherein it recites the limitation "overactivation of mTOR" in Claims 17/1. There is insufficient antecedent basis for this limitation in the claim. Further, it is unclear whether or not overactivation or a switch from quiescence into active cell cycling, is required for infringement since there are no positively stated active method steps whereby these effects are assessed.
Claim 21 is further indefinite because it attempts to further limit which genes are assessed for changes in gene expression (Claim 19). As stated above, there are no method steps for assessing gene expression in Claim 19, thus, without active steps it is entirely unclear whether or not assessing the expression of one or more of the listed claims is or is not required for infringement.
Claims 31 and 32 are indefinite wherein they recite: “wherein vasculogenesis in the vascular niche of the bone marrow hematopoietic microenvironment comprises communication paths between HSCs and BMECs that create effective cellular crosstalk, and wherein the communication paths between HSCs and BMECs comprise one or more of…” the listed factors. Claim 32 is further indefinite because it attempts to further limit the gene expression in BMECs. It is unclear whether or not changes in gene expression are required for infringement of the invention because there are no active method steps whereby expression is assessed. Therefore, further limiting the genes does not further clarify the scope of what is required for direct infringement. Rather, these claims appear to recite intended effects/results without imposing any methodological steps upon the scope of the invention. For purposes of applying prior art, the claims will be interpreted as reciting inherent features
For purposes of applying prior art, the claims will be interpreted as requiring: administering, alone or in combination with a stem cell co-therapy, a neutralizing anti-thrombospondin-1 mouse monoclonal antibody clone A4.1 (Thermofisher Scientific, Cat. No. MA5-13377); OR, an siRNA targeting TSP1comprising a sense strand comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 3, and an antisense strand comprising the sequence of SEQ ID NO: 2 or SEQ ID NO: 4, wherein the subjects include subjects with primary and secondary bone marrow failure, hematopoietic malignancies, solid tumors, congenital hematopoietic and immune deficiency states, and inherited metabolic disorders.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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 1 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Firlej et al., Cancer Res., 71(24): 7649-58, 2011.
Regarding claims 1 and 30, the “subject that requires reconstitution of their hematopoietic system” of instant claim 1, is defined in instant claim 30 as including “subjects with … solid tumors”. The Firlej et al. disclose solid prostate tumors express TSP1 and this stimulates migration of the cells (pg. 7652, second paragraph). Firlej et al. further demonstrate the TSP1-Ab1 antibody A4.1, of the instant claims, inhibits cancer cell migration (Figure 2E). Firlej et al. further teach anti-TSP1-siRNA (see attached Suppl Table 1) silenced TSP1 expression over 70% at the mRNA and protein levels and inhibit migration (Fig. 2A), with no effect on cell proliferation or apoptosis. The Firlej prior art teaches, “in radical prostatectomy specimens taken before any other treatment, we observed an increased TSP1 mRNA level… as compared with less invasive …staged cancers and a statistically higher tumoral TSP1 expression in patients who experienced tumor recurrence”. While the prior art does not teach administration of the A4.1 antibody or the anti-TSP-siRNA, it explicitly suggests that these may be treatments particularly when TSP1 expression on prostate biopsies provide incremental staging value in clinical practice, and improve identification of indolent tumors. The authors state: “TSP1 mRNA may also be of clinical interest to select patients at risk of PSA relapse” as adjuvant therapy.
It would have been obvious to a person having ordinary skill in the art to administer the A4.1 antibody to patients with solid prostate tumors. Motivation to do so is suggested within the Firlej et al. prior art reference wherein it suggests TSP1 expression can help identify indolent tumors and select patients at risk of relapse. In KSR International Co. v. Teleflex, Inc., the Supreme Court has stated that where there is a “pressure to solve a problem and a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense” (KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). In the instant case, the problem to be solved is treatment of solid tumors that require TSP-1 for migration, and the art demonstrates that there are a finite number of ways to inhibit tumor cell migration, namely, the TSP1-neutralizing antibody A4.1. Given the guidance and direction in the prior art reference, and the ordinary level of skill in the art of cancer treatment, a skilled artisan would have been able to administer A4.1 with predictable success.
Therefore, the method of the invention fails to distinguish over the methods disclosed in the prior art.
Claims 1 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Kopp et al., The Journal of Clinical Investigation, 116(12): 3277-3291, December 2006 in view of Firlej et al., Cancer Res., 71(24): 7649-58, 2011.
Regarding the method of Claim 1, the Kopp et al. prior art teaches TSP1 was the first endogenous inhibitor of angiogenesis (pg. 3277, third to last sentence). In the bone marrow, TSP1 is expressed in megakaryocytes and platelets (Figure 1) and the authors teach: “TSP1 has been shown to be a cytoadhesive molecule for hematopoietic stem cells” and “These data suggest that regional expression of TSPs could modulate marrow vascularity” (Figure 1 legend and pg. 3278, second column). The authors go on to demonstrate TSP double knock out mice “TSP-DKO mice exhibit increased bone marrow microvascular and megakaryocyte density as well as higher platelet levels in the steady state” (pg. 3279, last paragraph). Figure 3 of the reference teaches TSP deficiency enhances megakaryocyte repopulation of the bone marrow. The authors conclude: “Hemangiogenic regeneration and platelet recovery after myelosuppression are enhanced in TSP-deficient mice” (pg. 3280, last paragraph). Thus, the prior art reference teaches blockade of TSP plays a huge role in hemangiogenic regeneration of bone marrow.
While the prior art teaches TSP inhibition increases bone marrow hematopoiesis it does not disclose the mouse monoclonal antibody clone A4.1. The Firlej et al. prior art remedies this deficiency by disclosing the TSP1-Ab1 antibody A4.1, of the instant claims, inhibits the interaction between TSP1 and CD36 and blocks TSP1 activity (pg. 7652, last paragraph).
It would have been obvious to a person having ordinary skill in the art to substitute the A4.1 antibody, as taught by Firlej et al., for the TSP-knock out in the methods of Kopp et al. In KSR International Co. v. Teleflex, Inc., the Supreme Court has stated that where there is a “pressure to solve a problem and a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense” (KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). Simple substitutions of one element for another that does the same thing is well-within the technical grasp of a practitioner; particularly a practitioner who is capable of performing genetic knockdown, would find administration of an antibody to be routine experimentation. In the instant case, the problem to be solved is blockade of TSP-1 activity and the art demonstrates that there are a finite number of ways to achieve this and the commercially available TSP1-Ab1 antibody A4.1, of the instant claims was one. Motivation to use the antibody stems from the ethical concerns pertaining to genetic manipulation in species aside from animal models. Thus, one of ordinary skill could use the antibody to instead of the knockout methods of Kopp and could do so with predictable success of yielding hemangiogenic regeneration and platelet recovery after myelosuppression.
Therefore, the method of the instant claims is obvious in view of the combined teachings of the prior art, and through what could be achieved through routine substitution. Therefore, claims 1 and 30 are rejected.
Allowable Subject Matter
It should be noted that although Kopp et al. discloses the use of siRNA, it does not teach the sense/antisense constructs of instant claim 1, SEQ ID NOs: 1 or 3 (sense strand) and SEQ ID NOs: 2 or 4 (antisense).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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