DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 6, 8-11, 14-15, 17-18, 20, and 38-46 are currently pending in the application and under examination. An action on the merits follows. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application is a CON of U.S. Application No. 17/964,905, filed 12 October 2022, now U.S. Patent No. 12,115,194, which is a CON of U.S. Application No. 15/534,376, filed 08 June 2017, now U.S. Patent No. 11,491,188, which is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2015/081048, filed 22 December 2015, which claims priority to Australia AU2014905240, filed 23 December 2014.
A certified copy of the AU2014905240, filed 23 December 2014, was received with U.S. Application No. 15/534,376, to which the instant application claims priority.
Thus, the earliest possible priority for the instant application at present is 23 December 2014.
Information Disclosure Statement
The information disclosure statements filed 06 September 2024 and 08 April 2026 have been considered by the Examiner. Examiner notes the filing of IDS Size Fee Assertion for the IDS filed 08 April 2026, as required under 37 CFR 1.98, along with payment of the size fee as required under 37 CFR 1.17(v)(1). Note, however, that the threshold of 50 references corresponding to the size fee required under 37 CFR 1.17(v)(1) was met with the filing of the IDS filed 06 September 2024, which was before implementation of size fee requirement on 19 January 2025. No additional size fee thresholds were crossed with the IDS filed 08 April 2026.
Claim Objections
Claims 1 and 43 are objected to because of the following informalities:
Independent claim 1 recites, “a proximal left anterior descending (LAD) lesion” in line 4, which appears to be a typographical error for “a proximal left anterior descending artery (LAD) lesion”. Appropriate correction is required.
Claim 43 recites the abbreviation “HF-MACE” without first writing out the term for which "HF-MACE" is an abbreviation. Appropriate correction is required.
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.
Claims 1, 6, 8-11, 14-15, 17-18, 20, and 38-46 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.
Independent claim 1 has multiple issues of indefiniteness.
Claim 1 recites “a population of mesenchymal lineage precursor or stem cells and/or progeny thereof”, which is indefinite because it is unclear whether the stem cells are meant to encompass any stem cells or are meant to encompass specifically mesenchymal lineage stem cells. Dependent claims 6 similarly recites, “the mesenchymal lineage precursor or stem cells and/or progeny thereof” and dependent claims 14, 15, 38, 39, and 40 each similarly recite “the population of mesenchymal lineage precursor or stem cells and/or progeny thereof” with the same issues of indefiniteness as identified above for independent claim 1.
Claim 1 recites, “soluble factors derived therefrom” in lines 12-13, which is indefinite because it is unclear in what way the soluble factors are derived from the population of mesenchymal lineage precursor or stem cells and/or progeny thereof. For example, it is unclear whether the soluble factors are directly isolated from the recited cell population or whether the soluble factors are derivatized in some way from soluble factors isolated or otherwise obtained from the recited cell population. Additionally, if the soluble factors are isolated from the recited cell population, it is unclear whether the soluble factors are meant to be isolated from the cells themselves or from a supernatant/conditioned media in which the cells were incubated and whether or not the soluble factors are meant to be factors produced endogenously or exogenously by the cells. Further, it is unclear whether the soluble factors are meant to be derived from the population of mesenchymal lineage precursor stem cells, the progeny thereof, or both. Dependent claims 6, 14, and 15 similarly recite “soluble factors derived therefrom” with the same issues of indefiniteness as identified above for independent claim 1.
Claim 1 recites “a population of mesenchymal lineage precursor or stem cells and/or progeny thereof”, which is indefinite because it is unclear whether the stem cells are meant to be any stem cells or are meant to be mesenchymal lineage stem cells.
The term “increase” in independent claim 1 line 14 is a relative term which renders the claim indefinite. The term “increase” 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 specification teaches increases in LVEF from baseline values, but does not provide a limiting definition of the term “increase” or “to increase the subject’s LVEF” which would provide a reference to which the increased LVEF is relative.
As such, the metes and bounds of the claims cannot be determined.
Claim 8 recites, “wherein the subject has greater than about 4x upper limit of normal creatine kinase-MB and/or troponin and/or myoglobin” in lines 2-3, which has multiple issues of indefiniteness. Firstly, it is unclear whether the subject is meant to have the greater than about 4x upper limited of normal creatine kinase-MB and/or troponin and/or myoglobin before or after treatment. Secondly, the “upper limit of normal” has not been defined by the claim nor the specification, and so it is unclear what levels of creatine kinase-MB and/or troponin and/or myoglobin are encompassed by the claim. As such, the metes and bounds of the claim cannot be determined.
Claims 9 and 10 each recite, “wherein the subject has an infarct size” in lines 2 of each claim and claim 11 recites, “wherein the LVEF and/or infarct size” in line 2, which are indefinite because none of claims 9, 10, 11, nor 1 (upon which they all depend) recite wherein the subject has an infarct which can have an infarct size. As such, the metes and bounds of the claims cannot be determined.
Claims 17 and 18 each recite “comprising administering between… to… cells”, which is indefinite because it is unclear whether “between… to…” is meant to encompass the recited endpoints in that “between” implies that the range is exclusive of the endpoints, and would normally be accompanied by “and” as in “between x and y”, whereas “to” implies inclusivity and would normally be accompanied by “from” as in “from x to y”. Therefore, it is unclear whether Applicant intends to recite values between the two endpoints or whether Applicant means to recite values exclusive of the first recite value but inclusive of the second recited value. As such, the metes and bounds of the claims cannot be determined.
Claim 20 recites the limitation "the population of cells" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 20 has no prior recitation of a population of cells. Additionally, independent claim 1, upon which claim 20 depends, recites “a population of mesenchymal lineage precursor or stem cells and/or progeny thereof” but does not recite “a population of cells”. As such, the metes and bounds of the claim cannot be determined.
Claim 41 recites, “wherein administration decreases the size of the subject’s LV infarct by 10% or by 30%”, which has multiple issues of indefiniteness.
Firstly, neither claim 1 nor claim 41 have any prior recitation that the subject has an LV infarct and so it is unclear how the subject’s LV infarct size can be decreased.
Secondly, “decreases” is a relative term which renders the claim indefinite. The term “decrease” 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 specification teaches decreasing infarct size/volume relative to baseline values [0146, 0154], but does not provide a limiting definition of the term “decrease” or “decreases the size of the subject’s LV infarct” which would provide a reference to which the decreased infarct size is relative.
Thirdly, decreasing the size of the infarct “by 10% or by 30%” is further indefinite because it is unclear whether the percentages recited are meant to be relative changes in size or absolute changes in size in that the infarct size can be presented either as an absolute mass or as a fraction of the total LV mass. Accordingly, it is unclear whether “10%” or “30%” is meant to encompass a relative reduction of 10% or 30% such as relative to the starting infarct size (e.g., a 10% reduction from 5 g to 4.5 g or a 10% reduction from 5% to 4.5% of LV mass) or whether 10%” or “30%” is meant to encompass an absolute change of 10% or 30% such as relative to the starting infarct size (e.g., a 10% reduction from 30% to 20% of LV mass).
As such, the metes and bounds of the claim cannot be determined.
Claim 42 recites, “wherein administration improves the subject’s LV systolic function”. The term “improves” in claim 42 is a relative term which renders the claim indefinite. The term “improves” 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 specification teaches improving the subject’s LV systolic function without indicating a reference state [0156, 0158], and does not provide a limiting definition of the term “improves” or “improves the subject’s LV systolic function” which would provide a reference to which the improved LV systolic function is relative. As such, the metes and bounds of the claim cannot be determined.
Claim 43 recites, “wherein the subject’s risk of HF-MACE is reduced for a period of at least six months after the administration”. The term “reduced” in claim 43 is a relative term which renders the claim indefinite. The term “reduced” 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 specification teaches reducing HF-MACE without referencing relative to what the risk is reduced [0073], and does not provide a limiting definition of the term “reduced” or “the subject’s risk of HF-MACE is reduced” which would provide a reference to which the reduce HF-MACE risk is relative. As such, the metes and bounds of the claim cannot be determined.
Claims 44-46 each recite, “wherein the subject’s LVEF is increased” in lines 1-2 of each claim. The term “reduced” in claim 43 is a relative term which renders the claim indefinite. The term “increased” 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 specification teaches increasing LVEF from baseline [0151] or compared to non-responders [0153], but does not provide a limiting definition of the term “increased” or “the subject’s LVEF is increased” which would provide a reference to which the increased LVEF in the claim is relative. As such, the metes and bounds of the claim cannot be determined.
Claim Interpretations
Claim 1 recites, “c. persistent left ventricular dysfunction” in line 7 wherein the metes and bounds of the term “persistent” is not defined in the claim.
However, the specification teaches:
“[0082] In the context of the present disclosure the term “persistent left ventricular dysfunction” is used to define left ventricular dysfunction that persists over a period of time or series of measurements.”
Therefore, “persistent left ventricular dysfunction” has been interpreted to encompass any left ventricular dysfunction which is present for any duration of time.
Claims 39 and 40 each recite, “enriched for STRO-1+ cells” and “enriched for STRO-1bright cells”, respectively, in lines 4-5 of each claim. The instant specification teaches:
“[0046] The terms “enriched”, “enrichment” or variations thereof are used herein to describe a population of cells in which the proportion of one particular cell type or the proportion of a number of particular cell types is increased when compared with an untreated population of the cells (e.g., cells in their native environment). In one example, a population enriched for STRO-1+ cells comprises at least about 0.1% or 0.5% or 1% or 2% or 5% or 10% or 15% or 20% or 25% or 30% or 50% or 75% STRO-1+ cells. In this regard, the term “population of cells enriched for STRO-1+ cells” will be taken to provide explicit support for the term “population of cells comprising X% STRO-1+ cells”, wherein X% is a percentage as recited herein. The STRO-1+ cells can, in some examples, form clonogenic colonies, e.g. CFU-F (fibroblasts) or a subset thereof (e.g., 50% or 60% or 70% or 70% or 90% or 95%) can have this activity.
[0047] In one example, the population of cells is enriched from a cell preparation comprising STRO-1+ cells in a selectable form. In this regard, the term “selectable form” will be understood to mean that the cells express a marker (e.g., a cell surface marker) permitting selection of the STRO-1+ cells. The marker can be STRO-1, but need not be. For example, cells (e.g., mesenchymal precursor cells) expressing STRO-2 and/or STRO-3 (TNAP) and/or STRO-4 and/or VCAM-1 and/or CD146 and/or 3G5 also express STRO-1 (and can be STRO-1bright). Accordingly, an indication that cells are STRO-1+ does not mean that the cells are selected by STRO-1 expression. In one example, the cells are selected based on at least STRO-3 expression, e.g., they are STRO-3+ (TNAP+).”
As such, “enriched for STRO-1+ cells” and “enriched for STRO-1bright cells” has been interpreted to indicate any cell population which has any amount of STRO-1+ and/or STRO-1bright cells which is greater than the native fraction of STRO-1+ and/or STRO-1bright cells found in a freshly isolated population of cells comprising mesenchymal lineage precursor or stem cells. Further, enrichment of STRO-1+ and/or STRO-1bright cells is interpreted to encompass enrichment by selection for other factors expressed by STRO-1+ and/or STRO-1bright cells, including STRO-3.
Additionally, “STRO-1+ and/or STRO-1bright cells” has been interpreted to encompass cells which stain positive using the STRO-1 antibody and/or express the antigen detected by the STRO-1 antibody given that “STRO-1” is the name of an antibody and not the name of the antigen/protein detected by the antibody (see Fitter et al. 2017 which teaches that the identity of the antigen bound by the STRO-1 antibody was unknown until after filing of the instant application, wherein Fitter et al. published identification of the STRO-1 antigen as cell surface heat shock cognate 70 (HSC70) in 2017: Fitter et al. 2017, Stem Cells, 35(4), 940-951, abstract).
Claim 43 recites: “wherein the subject’s risk of HF-MACE is reduced for a period of at least six months after the administration” in lines 1-2. The specification recites: “Heart Failure-related Major Adverse Cardiac Events (HF-MACE, defined as heart failure hospitalization or death)” [0005]. For the purpose of examination, prior art which recites the decrease or prevention of heart failure hospitalization or death post-treatment will be considered to show reducing the risk of HF-MACE in the subject.
Claim Rejections - 35 USC § 112(a)- Written Description & New Matter
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.
Claim 41 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. This a new matter rejection.
Claim 41 fails to comply with the written description requirement because the claim text recites limitations which are not described in the specification and/or which encompass a claim breadth which is not supported by the specification. Additionally, the claim text recites limitations which were not taught nor recited in the original application as filed.
Claim 41, which was newly added in the preliminary amendment filed 19 November 2024, recites: “wherein administration decreases the size of the subject’s LV infarct by 10% or by 30%.” Note that the limitation of “wherein administration decreases the size of the subject’s LV infarct by 10% or by 30%” was additionally not included in the originally filed claims in either of the priority applications of U.S. Application Nos. 15/534,376 and 17/964,905 nor AU2014905240.
Note that it is not clear whether the 10% or 30% are absolute reductions in % of LV mass or volume or whether the 10% or 30% are meant to be relative reductions compared to some other state, such as a baseline state or a control administration (see 35 U.S.C. §112(b) rejection above).
There is no support in the original disclosure showing that the subject’s LV infarct size has been decreased by 30% as an absolute change in % of LV volume, mass, or other unit nor as a relative change in LV infarct size itself compared to any other prior state or control condition.
The specification recites: “Assuming a total mean myocardial mass of approximately 130g in these patients…, these values represent a very high risk population with approximately 30% infarct sizes at the time of therapeutic intervention” [0145]; “At the end of 6 months, subjects in the remestemcel-L group exhibited a decrease in LV infarct volume from a baseline value of 40.76 + 17.82 g to 26.6 + 12.94 g (mean + SD). This represented a -14.14 +13.94 g change” [0146]; and “…results indicate that remestemcel-L enhanced the natural endogenous healing process of infarct volume reduction by two-fold over 6 months relative to placebo, from approximately 30% infarct size at baseline to approximately 20% infarct size (assuming a mean LV mass of 130g) at 6 months” [0147]. This same degree of percent decrease is recited in para. [0148], pg. 28. That is, the specification describes a(n) absolute LV infarct size reduction of 10% of LV volume.
Note that a change from 30% to 20% of LV volume is an absolute change of 10% and a relative change of 33.3% (and not 30%). Further, using the infarct size values provided in g, the average absolute reduction in LV infarct volume (as indicated in specification even though the units are g) is 14.16 g, corresponding to a 34.7% (and not 30%) relative reduction.
Accordingly, the instant disclosure as filed does not 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, and the limitation “wherein administration decreases the size of the subject’s LV infarct by… 30%” constitutes new matter.
To overcome this rejection, Applicant may attempt to demonstrate (by means of argument or evidence) that the original disclosure establishes that he or she was in possession of the claim, the claim may be amended to recite a decrease in LV infarct size that is supported by the specification, or the claim describing a decrease of 30% in LV infarct size may be canceled.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1, 6, 8-11, 14-15, 17-18, 20, and 38-46 are rejected under 35 U.S.C. 103 as being unpatentable over Hare et al. [2012, Journal of the American Medical Association, 308(22), 2369-2379, including supplement]; in view of Williams & Hare [2011, Circulation Research, 109, 923-940]; Hare et al. [2009, Journal of the American College of Cardiology, 54(24), 2277-2286, IDS]; Galbraith et al. [2010, American Journal of Cardiology, 106(2), 162-166]; Krause et al. [2007, Stem Cells and Development, 16, 31-37]; and Psaltis et al. [2010, Journal of Cellular Physiology, 223(2), 530-540, IDS].
Regarding claim 1, Hare (2012) teaches a method of treating ischemic cardiomyopathy/ heart failure [abstract, pg 2372 col 3 ¶ 2] with reduced ejection fraction [pg 2371 col 1 ¶ 2] in a human subject characterized by the presence of: b) a left ventricular end systolic volume (LVESV) of greater than 70 ml [pg 2375 col 3 ¶ 1, Table 1, Figure 3, eTable 2, eFigure 2 (note that pg 2375 col 3 ¶ 1 teaches that the changes in “End-Systolic Volume” in Figure 3, eTable 2, and eFigure 2 are referring specifically to left ventricular remodeling and eFigure 2 also indicates that “End-Systolic Volume” is LV end-systolic volume]; c) persistent/chronic left ventricular dysfunction [abstract, pg 2370 col 2 ¶ 2]; and d) a left ventricular ejection fraction (LVEF) of less than 40% [Table 1, eTable 2], the method comprising administering to the subject a population of mesenchymal stem cells in an amount effective increase the subject’s LVEF [abstract, Figure 1, 3, eTable 3, eFigure 2].
Hare (2012) teaches that infarct locations in the patients included anterior locations [Table 1], does not explicitly teach wherein the subject is characterized by the presence of: a) a proximal left anterior descending (LAD) lesion.
Williams teaches delivery of MSCs to a variety of large animal models (including swine, sheep, and dogs) of MI in which left anterior descending (LAD) coronary artery occlusions/lesions are induced to inflict MI, including for both acute MI and chronic ischemic cardiomyopathy, wherein the MSC treatments resulted in increased EF in the MSC-treated animals [pg 931 col 1 ¶ 2-col2 ¶ 2, pg 932 col 1 ¶ 2, pg 933 col 1 ¶ 4, col 2 ¶ 2, 3, 4- pg 934 col 1 ¶ 2, col 1 ¶ 4- col 2 ¶ 1]. Williams also teaches the administration of hMSCs to human patients to treat ischemic heart failure wherein significant improvement in EF was detected in MSC-treated patients [pg 935 col 1 ¶ 5- col 2 ¶ 3].
Hare (2009) teaches administration of hMSCs to patients after acute myocardial infarction, wherein 15 (44.1%) of patients had a LAD coronary artery target vessel [Table 1], thereby teaching to administer hMSCs to patients having a LAD coronary artery lesion, wherein LVEF was increased [pg 2281 col 2 ¶ 1- pg 2282 col 1 ¶ 1, Table 3].
Therefore, given the teachings of Williams of extensive studies in large animal models for the treatment of chronic ischemic cardiomyopathy by administering MSCs in which LVEF was increased specifically in the MSC-treated animals, and the teachings of Hare (2009) to assess the LAD, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to modify the method of Hare (2012) to treat ischemic heart failure in patients with a left anterior descending (LAD) coronary artery lesion.
Galbraith teaches that patients with anterior acute ST-elevation myocardial infarction (STEMI) are at greater risk of in-hospital death, recurrent ischemia and STEMI, congestive heart failure, stroke, and 1-year mortality than patients with inferior or lateral STEMI, and that of the patients with anterior wall STEMI, those with more proximal occlusions in the left anterior descending (LAD) coronary artery have larger myocardial infarctions and worse outcomes [pg 162 col 1 ¶ 1, pg 165 col 2 ¶ 2]. Galbraith also teaches that patients with more proximally located LAD culprit lesions had larger myocardial infarctions and lower LVEF, including LVEFs at baseline less than 40% (i.e., average of 35.8%) [pg 164 col 1 ¶ 2- col 2 ¶ 1, Table 1, 2]. Therefore, in treating a subject having a LAD arterial lesion, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to treat patients having proximal LAD arterial lesions in a method that increases LVEF in the subject, and/or an ordinarily skilled artisan at the time of filing the instant application would have expected that a patient population wherein subjects have reduced LVEF <40% would necessarily include patients which have proximal LAD arterial lesions.
Regarding claim 6, Hare (2012), Williams, Hare (2009), and Galbraith teach the limitations of claim 1. Hare (2012) teaches that the time since last myocardial infarction (MI) averaged 9 years for the allogenic MSC group and 12.8 years for the autologous MSC group, but does not teach specifically to administer hMSCs between about 1 and 7 days post-myocardial infarction.
Hare (2009) teaches inclusion of only patients who had an MI within 1-10 days prior to randomization and subsequence injection of hMSCs [pg 2278 col 2 ¶ 4], and that the time after MI to infusion of study agent ranged from 1 to 10 days [Figure 1].
Williams teaches the delivery of MSCs to large animal models 3, 5, or 7 days following an acute MI, wherein LVEF improved in the MSC-treated animals compared to placebo controls [pg 932 col 1 ¶ 2- pg 933 col 1 ¶ 1, pg 934 col 2 ¶ 3]. Williams also teaches administering hMSCs to humans with acute MI, wherein MSC-treated patients demonstrated improved EF at 3 months [pg 935 col 1 ¶ 3-4].
Therefore, given the teachings of Hare (2009) to administer hMSCs within 1-10 days following an acute MI, wherein treated patients showed a significant increase in LVEF compared to controls, and the teachings of Williams to administer MSCs to large animal models at 3-7 days following an acute MI, wherein treated animals demonstrated improved/increased LVEF compared to controls, the ordinarily skilled artisan at the time of filing the instant application would have been motivated to administer MSCs to a patient between about 1 and 10 days, including between about 3-7 days, post-myocardial infarction.
Regarding claim 8, Hare (2012) teaches that patients had baseline serum troponin I levels of 0.0 and 0.1 for the allogenic MSC and autologous MSC groups, respectively, which increased to 0.8 ng/mL and 0.9 ng/mL 12 hours following injection of allogenic MSCs and autologous MSCs, respectively [Table 2]. Hare (2012) further teaches that the upper limit of normal for serum troponin I is 0.04-0.07 ng/mL [pg 2373 col 1 ¶ 2]; therefore, Hare (2012) teaches wherein the patients have greater than about 4x the upper limit of normal troponin.
Regarding claim 9, Hare (2012) teaches wherein the patients have an average MI scar of 9.3 +/- 3.8% and 10.1 +/- 5.9% of the LV mass for the allogenic and autologous groups, respectively [Table 1], and also teaches wherein the patients had baseline average MI scars of 6.99-14.43% of the LV mass [eTable 2], thereby teaching to administer MSCs to patients which have an infarct size between about 10% and 25% of the left ventricle.
Regarding claim 10, Hare (2012) teaches that a larger infarct at baseline resulted in a larger reduction in infarct size [pg 2376 col 2 ¶ 1].
Hare (2012) does not teach wherein the subject has an infarct size greater than about 18.5 % of the left ventricle.
Krause teaches intravenous delivery of autologous MSCs to a swine model of myocardial infarction 48 hours post proximal left anterior descending artery (LAD) occlusion, wherein the labeled MSCs migrated in the peri-infarct region, resulting in smaller infarct size of 19% post-treatment in the treated animals vs 32% in the control animals [pg 32 col 2 ¶ 2, 3- pg 33 col 1 ¶ 1, abstract, Table 1, Figure 1]. Accordingly, Krause teaches that infarct sizes greater than about 19% of the left ventricle can be reduced by administration of MSCs.
Given the teachings of Hare (2012) that larger infarct sizes result in larger reductions in infarct size upon treatment with hMSCs in human patients and the teachings of Krause that infarct sizes greater than 19% can be reduced by administration of MSCs in a large animal model, the ordinarily skilled artisan at the time of filing the instant application would have been motivated to treat subjects having infarct sizes of greater than about 19% of the left ventricle by the method of Hare (2012) to reduce the infarct size in those subjects.
Regarding claim 11, Hare (2012) teaches using multidetector CT to measuring the LVEF and/or infarct size, but that cardiac magnetic resonance imaging (cMRI) is a highly valuable modality which can be safely performed in many patients with cardiac rhythm management devices [pg 2371 col 3 ¶ 1, pg 2377 col 2 ¶ 4, eTable 2].
Hare (2009) teaches using cMRI to measure left ventricular ejection fraction [abstract, pg 2279 col 2 ¶ 2]. Williams also teaches the use of cMRI to measure EF and scar size in large animal studies [Table 2, pg 932 col 1 ¶ 2, col 2 ¶ 2, pg 933 col 1 ¶ 1-2, col 2 ¶ 3, pg 934 col 1 ¶ 3, col 2 ¶ 2] and in human subjects [pg 935 col 2 ¶ 1. Figure 6].
Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use cardiovascular magnetic resonance imaging to measure the LVEF and/or infarct size in a patient.
Regarding claims 14-15 and 38, Hare (2012) teaches administration of hMSCs to subjects by transendocardial stem cell injection (TESI)/intracardiac administration [abstract, pg 2370 col 1 ¶ 2-col 3 ¶ 1].
Additionally, Williams teaches that intravenous infusion of MSCs is the easiest and most practical method for delivery because it only requires peripheral venous access [pg 931 col 1 ¶ 2]. Williams further teaches improvement of LVEF in swine injected intravenously with MSCs [pg 931 col 2 ¶ 2]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to administer the MSCs systemically via an intravenous administration.
Regarding claims 17, Hare (2012) teaches administration of 20 million (2 x 107), 100 million (1 x 108), or 200 million (2 x 108) human mesenchymal stem cells [abstract]. Hare (2012) further teaches that LVEF was increased on average at each dose of 2 x 107 cells and 1 x 108 cells and in a subset of subjects at 2 x 108 cells [eFigure 2].
Regarding claims 18, Hare (2009) teaches administration of 0.5, 1.6, and 5 million cells/ kg, which for an average adult human of approximately 80 kg, amounts to about 4 x 107, 1.28 x 108, and 4 x 108 cells [abstract]. Hare (2009) also teaches that these doses were sufficient to increase LVEF [pg 2281 col 2 ¶ 2, Table 3]. Therefore, an ordinarily skilled artisan at the time of filing would have been motivated to administer dose of about 1.28 x 108 to about 4 x 108 MSCs to increase LVEF in a human subject.
Regarding claim 20, Hare (2012) teaches expansion of MSCs in culture prior to administration [pg 2370 col 1 ¶ 2, pg 2371 col 1 ¶ 3, pg 2372 col 3 ¶ 3, eMethods pg 1 ¶ 5].
Regarding claims 39-40, Hare (2012), Williams, Hare (2009), and Galbraith teach the limitations of claims 1 and 20, but do not teach to enrich for STRO-1+ or STRO-1bright cells prior to culture expansion of the MSCs.
However, Williams teaches STRO-3+ mesenchymal precursor cells injected directly into the infarct border zone 1 hour after MI, wherein STRO-3+ MPCs are a subset of BM-MSCs with extensive capacity for proliferation and differentiation [pg 925 col 2 ¶ 4, pg 933 col 1 ¶ 4]. As discussed above, the instant specification teaches that “enriched for STRO-1+ and/or STRO-1bright cells” encompasses any enrichment process which increases the amount of STRO-1+ and/or STRO-1bright cells within the cell population, including selection for co-expressed markers such as STRO-3. As such, Williams teaches administration of cells which have been enriched for STRO-1+ cells.
Additionally, Psaltis teaches that enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations [title]. Psaltis also teaches that compared to plastic adherence-isolated MSC, STRO-1 enriched MSC (STRO-1-MPC) displayed greater clonogenicity, proliferative capacity, multilineage differentiation potential, and mRNA expression of MSC-related transcripts [abstract]. Psaltis further teaches that paracrine responses were enhanced by using supernatant from STRO-1Bright MPC and diminished with STRO-1Dim conditioned media [abstract]. Psaltis additionally teaches that transplantation of human STRO-1bright MPC, but not STRO-1 depleted cells, resulted in improved myocardial contractility and vascular density in athymic nude rate model of myocardial infarction [pg 539 col 1 ¶ 3]. Psaltis teaches that prospective isolation gives rise to mesenchymal progeny that maintain a higher proportion of immature precursor cells compared to traditional plastic adherence-isolation and that enrichment for STRO-1 is also accompanied by increased expression of cardiovascular-relevant cytokines and enhanced trophic activity, such that immunoselection provides a strategy for improving the cardiovascular reparative potential of MSCs [abstract]. Therefore, given the teachings of Psaltis that enriching a population of MSCs for STRO-1+ cells generates cells with greater clonogenicity, proliferative capacity, multilineage differentiation potential, and mRNA expression of MSC-related transcripts and provides a strategy for improving the cardiovascular reparative potential of MSCs, an ordinarily skilled artisan would have been motivated to enrich MSCs for STRO-1 antigen expression prior to culture expansion of a population of MSCs for treating a cardiac condition. Additionally, an ordinarily skilled artisan at the time of filing would have been further motivated to enrich for STRO-1bright cells to enhance cardiac-stimulating paracrine effects of the MSCs and to improve myocardial contractility and vascular density following MI.
Regarding claim 41, Hare (2012) teaches that subjects treated with allogenic hMSCs had an average reduction in MI size of 34.7% (i.e., 20.02 g at baseline and 13.07 g at 13-months follow-up) and subjections treated with autologous hMSCs had an average reduction in MI size of 38.5% (24.34 g at baseline and 14.96 g at 13-month follow-up) [eTable 2]. Hare (2012) also teaches that the reduction in scar as a % of LV mass for the allogenic group was 3.86% absolute reduction, corresponding to a relative reduction of 41%, and for the autologous group was 4.79% absolute reduction, corresponding to a relative reduction of 44.7%. Hare also teaches individual absolute changes in MI size, which range from about +5 g to about -30 g, but does not indicate what percentage the changes represent [Figure 3, eFigure 2].
Hare (2012) does not specifically teach exactly 10% or exactly 30% reduction in infarct size.
However, Williams teaches that swine treated with transendocardial allogenic MSC injection showed that MSC therapy resulted in a 17% or a 30% reduction in scar size [pg 932 col 2 ¶ 2, pg 933 col 1 ¶ 2, Figure 5].
Therefore, given the teachings of Hare (2012) of variable reductions in infarct size which average about 38% relative reduction and about 4% absolute reduction relative to LV size, and the teachings of Williams of a swine treated with allogenic MSC that specifically reduced infarct scar size by 30%, an ordinarily skilled artisan at the time of filing the instant application would expect that at least some subjects treated by the method of Hare (2012) would exhibit decreases in the size of the subject’s LV infarct by 10% or by 30%.
Regarding claim 42, Hare (2012) teaches that administration of hMSCs decreases/improves the subject’s LV systolic function [pg 2376 col 3 ¶ 1-2, pg 237 col 1 ¶ 3, col 2 ¶ 3, Figure 3, 4, eFigure 2].
Regarding claim 43, Hare (2012) teaches that subjects administered allogenic MSCs had a 20.0% incidence/risk of MACE and subjects administered autologous MSCs had a 26.7% incidence/risk of MACE over 12 months follow-up [eTable 1]. Hare (2012) does not have a placebo control group to compare MACE risk against to determine whether administration reduced the risk.
However, Hare (2009) teaches that the serious adverse event rate was 23.5% in the hMSC group and 31.6% in the placebo group [pg 2280 col 2 ¶ 5], indicating a reduction in risk for serious adverse events in the hMSC-treated subjects. Hare (2009) does not explicitly recite a heart failure-related major adverse cardiac event statistic, but does indicate that no deaths occurred in either group over the course of the study (i.e., at least within 6 months following administration), and that the hospitalization rate was 31.6% at an average of 66 days after discharge in the placebo group versus 23.5% at an average of 120 days after discharge in the hMSC group, indicating a reduction in HF-MACE in the hMSC-treated group compared to the placebo-treated group [pg 2280 col 2 ¶ 3, 5, Table 2].
Therefore, given the teachings of Hare (2009) that hMSC treatment reduced the risk of major adverse cardiac events in patients following MI compared to placebo, and the teachings of Hare (2012) of MACE rates which are lower than those taught by Hare (2009) for hMSC-treated subjects, an ordinarily skilled artisan at the time of filing the instant application would expect that the method of Hare (2012) which similarly administers hMSC to patients having MI-induced lesions would likewise reduce the risk of MACE for at least the 6 month follow-up period taught by Hale (2009).
Regarding claims 44-46, Hale (2012) teaches subjects whose LVEF is increased by between 6 LVEF units (i.e., 6%) and 15 LVEF units (i.e., 15%) following administration of hMSCs, wherein the LVEF was increased 13 months after administration [Figure 3, 4, eFigure 2].
Hale (2012) does not specifically teach that the LVEF was also increased at 6 months after administration.
However, Hale (2009) teaches 6 month follow-up data for increased LVEF in patients administered hMSCs, wherein LVEF was increased by 6.7% over baseline in hMSC-treated patients [pg 2282 col 1 ¶ 1].
Accordingly, given the increased LVEF at 13 months following administration taught by Hale (2012), and the increased LVEF at 6 months following administration taught by Hale (2009), an ordinarily skilled artisan would expect that subjects treated by the method of Hale (2012) would also have increased LVEF 6 months following administration.
Given the motivation taught by Williams and Hare (2009) to modify the method of Hare (2012) to treat ischemic heart failure in patients with a left anterior descending (LAD) coronary artery lesion; the motivation taught by Galbraith to treat patients having proximal LAD arterial lesions in a method that increases LVEF in the subject, and/or the expectation that a patient population wherein subjects have reduced LVEF <40% would necessarily include patients which have proximal LAD arterial lesions; the motivation taught by Hare (2009) and Williams to administer MSCs to a patient between about 1 and 10 days, including between about 3-7 days, post-myocardial infarction; the motivation taught by Hare(2012) and Krause to treat subjects having infarct sizes of greater than about 19% of the left ventricle by the method of Hare (2012) to reduce the infarct size in those subjects; the motivation taught by Hare (2012), Hare (2009), and Williams to use cardiovascular magnetic resonance imaging to measure the LVEF and/or infarct size in a patient; the motivation taught by Williams to administer the MSCs systemically via an intravenous administration; the motivation taught by Hare (2009) to administer dose of about 1.28 x 108 to about 4 x 108 MSCs to increase LVEF in a human subject; the motivations taught by Psaltis to enrich MSCs for STRO-1 antigen expression prior to culture expansion of a population of MSCs for treating a cardiac condition and to enrich for STRO-1bright cells to enhance cardiac-stimulating paracrine effects of the STRO-1+ MSCs and to improve myocardial contractility and vascular density following MI; the expectation taught by Hare (2012) and Williams that at least some subjects treated by the method of Hare (2012) would exhibit decreases in the size of the subject’s LV infarct by 10% or by 30%; the expectations taught by Hare (2012) and Hare (2009) that the method of Hare (2012) would reduce the risk of MACE for at least a 6 month follow-up period and that subjects treated by the method of Hale (2012) would have increased LVEF 6 months following administration; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the method of Hale (2012) to treat ischemic heart failure in patients with a proximal left anterior descending (LAD) coronary artery lesion and an infarct size greater than about 19%, to administer a dose of about 1.28 x 108 to about 4 x 108 MSCs enriched for STRO-1bright prior to culture expansion to the patient between about 1 and 7 days post-myocardial infarction, to measure LVEF and/or infarct size using cardiac magnetic resonance imaging, to administer the MSCs systemically via an intravenous administration to achieve the instantly claimed outcomes of increased LVEF at 6 months, infarct size reduction of 10% or 30%, and reduced risk of HR-MACE for at least 6 months with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 1, 6, 8-11, 14-15, 17-18, 20, and 38-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,712,452, hereafter referred to as the ‘452 patent.
The claimed subject matter of the instant application is:
Claim 1. A method of treating ischemic heart failure with reduced ejection fraction in a human subject characterized by the presence of:
a. a proximal left anterior descending (LAD) lesion;
b. a left ventricular end systolic volume (LVESV) of greater than 70 ml;
c. persistent left ventricular dysfunction; and
d. a left ventricular ejection fraction (LVEF) of less than 40%, the method comprising administering to the subject a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom, or a combination of any of the foregoing in an amount effective to increase the subject's LVEF.
Claim 6 further recites wherein the cells or factors are administered following MI.
Claim 38 recites administering the cells to the subject by intracardiac administration.
Claim 39 further recites wherein the cells have been culture expanded from a population of mesenchymal lineage precursor or stem cells enriched for STRO-1+ cells.
Claim 42 recites wherein administration improves the subject’s LV systolic function.
Claim 43 further recites wherein the subject’s risk of HF-MACE is reduced for a period of at least six months after the administration.
The claimed subject matter of the ‘452 patent is:
Claim 1. A method for treating chronic heart failure due to left ventricular systolic dysfunction in a human subject characterized by:
(i) an elevated baseline left ventricular end systolic volume (LVESV) of greater than 100 mL, and
(ii) a baseline left ventricular ejection fraction (LVEF) of less than or equal to 35%,
the method comprising administering to the myocardium of the human subject's heart a population of about 75-150 million mesenchymal lineage precursor cells (MPCs) expressing STRO-1+ and STRO-3+ so as to improve the human subject's LVESV and left ventricular end diastolic volume (LVEDV) by: (a) reducing the LVESV by at least 8 mL relative to the subject's baseline LVESV volume; and (b) reducing the LVEDV by at least 10 mL relative to the subject's baseline LVEDV volume, so as to treat the subject's chronic heart failure, wherein (a) and (b) are measured at 6 months after administration of the MPCs.
Claim 6. The method according to claim 1, wherein the heart failure is due to hypertension, ischemic or non-ischemic cardiomyopathy, myocarditis, obesity, or diabetes.
Claim 11. The method according to claim 1, wherein the MPCs are STRO-1bright cells.
The instant claims are not patentably distinct from the ‘452 patent claims because, as demonstrated above in the claim sets from each application, a method for treating chronic heart failure due to left ventricular systolic dysfunction in a human subject, recited in the ‘452 patent claims, exhibits minor species modifications which anticipate and/or encompass the instantly claimed method for treating ischemic heart failure with reduced ejection fraction in a human subject. Although “ischemic heart failure with reduced ejection fraction in a subject having persistent left ventricular dysfunction” is a species of “chronic heart failure due to left ventricular systolic dysfunction”, the subject characteristics of the ‘452 patent claims are species of the instantly recited subject characteristics, such that an LVESV of >100 mL is a species of the instantly claimed LVESV >70 mL and a baseline left ventricular ejection fraction (LVEF) of less than or equal to about 35% is a species of LVEF < 40%.
Further, the ‘452 patent claims recite wherein the chronic heart failure is due to ischemic cardiomyopathy.
Additionally, to the extent that claimed outcomes differ between the instant application claims and the ‘452 patent claims, they represent consequences of the same active method step of administering the same mesenchymal lineage precursor cells (MPCs) expressing STRO-1+ to the same subject, and as such would be expected to also result from the instantly claimed invention.
Accordingly, the ‘452 patent claims anticipate, encompass, and render obvious the instantly claimed invention.
Claims 1, 6, 8-11, 14-15, 17-18, 20, and 38-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12,303,536, hereafter referred to as the ‘536 patent.
The claimed subject matter of the instant application is:
Claim 1. A method of treating ischemic heart failure with reduced ejection fraction in a human subject characterized by the presence of:
a. a proximal left anterior descending (LAD) lesion;
b. a left ventricular end systolic volume (LVESV) of greater than 70 ml;
c. persistent left ventricular dysfunction; and
d. a left ventricular ejection fraction (LVEF) of less than 40%, the method comprising administering to the subject a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom, or a combination of any of the foregoing in an amount effective to increase the subject's LVEF.
Claim 6 further recites wherein the cells or factors are administered following MI.
Claim 17. The method of claim 1 comprising administering between 1 x 108 to 8 x 108 cells.
Claim 18. The method of claim 17 comprising administering between 1.2 x 108 to 4 x 108 cells.
Claim 38 recites administering the cells to the subject by intracardiac administration.
Claim 39 further recites wherein the cells have been culture expanded from a population of mesenchymal lineage precursor or stem cells enriched for STRO-1+ cells.
Claim 42 recites wherein administration improves the subject’s LV systolic function.
Claim 43 further recites wherein the subject’s risk of HF-MACE is reduced for a period of at least six months after the administration.
The claimed subject matter of the ‘536 patent is:
Claim 1. A method for treating chronic heart failure due to left ventricular systolic dysfunction in a human subject characterized by:
(i) a baseline left ventricular end systolic volume (LVESV) of greater than 100 mL; and
(ii) a baseline left ventricular ejection fraction (LVEF) of less than or equal to about 35%; wherein the method comprises administering to the myocardium of the human subject's heart, a population of culture expanded STRO-1+ mesenchymal lineage precursor cells (MPCs), so as to decrease the human subject's baseline LVESV or decrease the human subject's baseline left ventricular end diastolic volume (LVEDV) by at least 8 mL 6 months after administration of the MPCs.
Claim 2. The method according to claim 1, wherein the MPCs have been culture expanded from a population of STRO-1+ and STRO-3+ cells.
Claim 3. The method of claim 1, wherein: (i) the baseline LVESV is due to acute myocardial infarction; or (ii) the baseline LVESV is due to chronic congestive heart failure.
Claim 7. The method according to claim 1 wherein the heart failure is due to hypertension, ischemic or non-ischemic cardiomyopathy, myocarditis, obesity, or diabetes.
Claim 9. The method according to claim 1, comprising administering a population of culture expanded STRO-1 + MPCs from 1×106 to 8×108 to the subject in a single dose or over multiple doses.
Claim 10. The method of claim 1, wherein the human subject is administered a population of culture expanded STRO-1+ MPCs of about 1.50×106 MPCs.
Claim 13. The method according to claim 1, wherein the population of STRO-1+ MPCs are STRO-1bright cells.
The instant claims are not patentably distinct from the ‘536 patent claims because, as demonstrated above in the claim sets from each application, method for treating chronic heart failure due to left ventricular systolic dysfunction in a human subject, recited in the ‘536 patent claims, exhibits minor species modifications that anticipates and/or encompasses the instantly claimed method for treating ischemic heart failure with reduced ejection fraction in a human subject. Although “ischemic heart failure with reduced ejection fraction in a subject having persistent left ventricular dysfunction” is a species of “chronic heart failure due to left ventricular systolic dysfunction”, the subject characteristics of the ‘536 patent claims are species of the instantly recited subject characteristics, such that an LVESV of >100 mL is a species of the instantly claimed LVESV >70 mL and a baseline left ventricular ejection fraction (LVEF) of less than or equal to about 35% is a species of LVEF < 40%.
Further, the ‘536 patent claims recite wherein the chronic heart failure is due to ischemic cardiomyopathy.
Additionally, to the extent that claimed outcomes differ between the instant application claims and the ‘536 patent claims, they represent consequences of the same active method step of administering the same mesenchymal lineage precursor cells (MPCs) expressing STRO-1+ to the same subject, and as such would be expected to also result from the instantly claimed invention.
Accordingly, the ‘536 patent claims anticipate, encompass, and render obvious the instantly claimed invention.
Claims 1, 6, 8-11, 14-15, 17-18, 20, and 38-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,491,188, hereafter referred to as the ‘188 patent.
The claimed subject matter of the instant application is:
Claim 1. A method of treating ischemic heart failure with reduced ejection fraction in a human subject characterized by the presence of:
a. a proximal left anterior descending (LAD) lesion;
b. a left ventricular end systolic volume (LVESV) of greater than 70 ml;
c. persistent left ventricular dysfunction; and
d. a left ventricular ejection fraction (LVEF) of less than 40%, the method comprising administering to the subject a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom, or a combination of any of the foregoing in an amount effective to increase the subject's LVEF.
Claim 6 further recites wherein the cells or factors are administered following MI.
Claim 9 recites wherein the subject has an infarct size between about 10 - 25 % of the left ventricle.
Claim 10 recites wherein the subject has an infarct size greater than about 18.5 % of the left ventricle.
Claim 41 recites wherein administration decreases the size of the subject's LV infarct by 10% or by 30%.
Claim 42 recites wherein administration improves the subject’s LV systolic function.
Claim 43 further recites wherein the subject’s risk of HF-MACE is reduced for a period of at least six months after the administration.
The claimed subject matter of the ‘188 patent is:
Claim 1. A method for reducing the risk of heart failure-related major adverse cardiac events (HF-MACE) in a human subject characterized by the following: a) a left ventricular (LV) infarct, the size of which is greater than 18.5% of the left ventricle as measured by cardiovascular magnetic resonance imaging (cMR); b) a proximal left anterior descending (LAD) arterial lesion; c) a left ventricular end systolic volume (LVESV) of greater than 70 ml; d) persistent left ventricular dysfunction; and e) a left ventricular ejection fraction (LVEF) of less than 40%, which comprises administering to the subject a population of mesenchymal lineage precursor or stem cells, progeny thereof, or a combination of any of the foregoing in an amount effective to (i) decrease the size of the subject's LV infarct and (ii) improve the subject's LV systolic function so as to thereby reduce the subject's risk of HF-MACE for a period of at least six months after the administration.
The instant claims are not patentably distinct from the ‘188 patent claims because, as demonstrated above in the claim sets from each application, the method for reducing the risk of heart failure-related major adverse cardiac events (HF-MACE) in a human subject, recited in the ‘188 patent claims recites the same subject characteristics and the same active method steps as the instant claims.
Additionally, to the extent that claimed outcomes differ between the instant application claims and the ‘188 patent claims, they represent consequences of the same active method step of administering the same population of mesenchymal lineage precursor or stem cells and/or progeny thereof to the same subject, and as such would be expected to also result from the instantly claimed invention.
Accordingly, the ‘188 patent claims anticipate and/or encompass and render obvious the instantly claimed invention.
Claims 1, 6, 8-11, 14-15, 17-18, 20, and 38-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12,115,194, hereafter referred to as the ‘194 patent.
The claimed subject matter of the instant application is:
Claim 1. A method of treating ischemic heart failure with reduced ejection fraction in a human subject characterized by the presence of:
a. a proximal left anterior descending (LAD) lesion;
b. a left ventricular end systolic volume (LVESV) of greater than 70 ml;
c. persistent left ventricular dysfunction; and
d. a left ventricular ejection fraction (LVEF) of less than 40%, the method comprising administering to the subject a population of mesenchymal lineage precursor or stem cells and/or progeny thereof and/or soluble factors derived therefrom, or a combination of any of the foregoing in an amount effective to increase the subject's LVEF.
Claim 6 further recites wherein the cells or factors are administered following MI.
Claim 9 recites wherein the subject has an infarct size between about 10 - 25 % of the left ventricle.
Claim 10 recites wherein the subject has an infarct size greater than about 18.5 % of the left ventricle.
Claim 41 recites wherein administration decreases the size of the subject's LV infarct by 10% or by 30%.
Claim 42 recites wherein administration improves the subject’s LV systolic function.
Claim 43 further recites wherein the subject’s risk of HF-MACE is reduced for a period of at least six months after the administration.
The claimed subject matter of the ‘194 patent is:
Claim 1. A method for reducing the risk of heart failure-related major adverse cardiac events (HF-MACE) in a human subject characterized by the following:
a) a left ventricular (LV) infarct;
b) a proximal left anterior descending (LAD) arterial lesion;
c) a left ventricular end systolic volume (LVESV) of greater than 70 ml;
d) persistent left ventricular dysfunction; and
e) a left ventricular ejection fraction (LVEF) of less than 40%,
which comprises administering to the subject a population of mesenchymal lineage precursor or stem cells and/or progeny thereof, or a combination of any of the foregoing in an amount effective to: (i) decrease the size of the subject's LV infarct; and (ii) improve the subject's LV systolic function so as to thereby reduce the subject's risk of HF-MACE for a period of at least six months after the administration.
The instant claims are not patentably distinct from the ‘194 patent claims because, as demonstrated above in the claim sets from each application, the method for reducing the risk of heart failure-related major adverse cardiac events (HF-MACE) in a human subject, recited in the ‘194 patent claims, recites the same subject characteristics and the same active method steps as the instant claims.
Additionally, to the extent that claimed outcomes differ between the instant application claims and the ‘194 patent claims, they represent consequences of the same active method step of administering the same population of mesenchymal lineage precursor or stem cells and/or progeny thereof to the same subject, and as such would be expected to also result from the instantly claimed invention.
Accordingly, the ‘194 patent claims anticipate and/or encompass and render obvious the instantly claimed invention.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
Prosecution Insights