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 .
Applicant's election without traverse of Group II, claims 2-24 in the reply filed on 4 November 2025 is acknowledged. Claims 3 and 4 have been amended. Claim 1 has been withdrawn. Claims 2-24 are currently pending and under examination.
This application claims benefit of priority to U.S. Provisional Application No. 63/173960, filed April 12, 2021; U.S. Provisional Application No. 63/134535, filed January 06, 2021; and U.S. Provisional Application No. 63/075686, filed September 08, 2020.
Claim Objections
Claims 2-4, 6, 9, 11, 14, 17, 19, 21, and 24 are objected to because of the following informalities: both “allogeneic” and “allogenic” are used to refer to the same term in these claims. The same term should be spelled consistently throughout the claims.
Claims 6, 11, 14, 17, and 24 recite the term “cerebral spinal fluid.” This term is misspelled and should instead be “cerebrospinal fluid.”
Appropriate correction is required.
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 2-24 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 2 recites the limitation "the subject" in line 3. There is insufficient antecedent basis for this limitation in the claim. No subject is previously recited in the claim.
Further, claim 2 recites:
A method for treating Alzheimer's disease (AD) or inhibiting AD disease progression, wherein the method comprises administering a composition comprising a therapeutically effective amount of allogeneic mesenchymal stem cells (MSCs) to the subject.
This claim is indefinite, because as currently written, it is unclear if the subject being administered the composition is required to have Alzheimer's disease or not. To overcome this rejection, it is suggested that the claim be amended to indicated that the method is to treat “a subject in need thereof,” or the like.
Claim 3 recites the limitations “the concentration of a biomarker or biomarkers” in line 2, and "the subject suffering from symptoms of AD" in lines 2-3. There is insufficient antecedent basis for these limitations in the claim. No concentration of biomarker(s), or subject suffering from symptoms of AD are previously recited in the claims.
Claim 4 recites the limitations “the cognitive function” in line 2, and "the subject suffering from symptoms of AD" in line 2. There is insufficient antecedent basis for these limitations in the claim. No cognitive function or subject suffering from symptoms of AD are previously recited in the claims.
Claim 6 recites the limitations “the serum, plasma, cerebral spinal fluid or blood” in line 2, and "the subject in need thereof" in line 2. There is insufficient antecedent basis for these limitations in the claim. No serum, plasma, cerebral spinal fluid or blood, and no subject in need thereof are previously recited in the claims.
Claim 9 recites the limitations “the serum, plasma, cerebral spinal fluid or blood” in line 2, and "the subject in need thereof" in line 2. There is insufficient antecedent basis for these limitations in the claim. No serum, plasma, cerebral spinal fluid or blood, and no subject in need thereof are previously recited in the claims.
Claim 11 recites the limitations “the serum, plasma, cerebral spinal fluid or blood” in line 2, and "the subject in need thereof" in line 2. There is insufficient antecedent basis for these limitations in the claim. No serum, plasma, cerebral spinal fluid or blood, and no subject in need thereof are previously recited in the claims.
Regarding claim 13, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Here, it is unclear if the inflammation signaling molecules following “such as” are intended to be required or not.
Claim 14 recites the limitations “the serum, plasma, cerebral spinal fluid or blood” in line 2, and "the subject in need thereof" in lines 2-3. There is insufficient antecedent basis for these limitations in the claim. No serum, plasma, cerebral spinal fluid or blood, and no subject in need thereof are previously recited in the claims.
Claim 17 recites the limitations “the serum, plasma, cerebral spinal fluid or blood” in line 2, and "the subject in need thereof" in line 2. There is insufficient antecedent basis for these limitations in the claim. No serum, plasma, cerebral spinal fluid or blood, and no subject in need thereof are previously recited in the claims.
Claim 18 recites the percentage by which VEGF is decreased, following administration. However, claim 17, from which claim 18 depends, indicates that the VEGF concentration is increased. As such, claim 18 is indefinite, because it is unclear how the same component is expected to be both increased and decreased as a result of performance of the same method.
Claim 19 recites the limitations “the change” in line 2, "the size” in line 2, and “the subject’s brain” in line 2. There is insufficient antecedent basis for these limitations in the claim. No change, size, or subject’s brain are previously recited in the claims.
Claim 20 recites the limitations “the hippocampus” in line 3, and "the corticoamygdaloid transition” in line 4. There is insufficient antecedent basis for these limitations in the claim. No hippocampus or corticoamygdaloid transition are previously recited in the claims.
Claim 21 recites the limitation "the corticoamygdaloid transition” in line 2. There is insufficient antecedent basis for this limitation in the claim. No corticoamygdaloid transition is previously recited in the claims.
Claims 21 and 24 recite “allogeneic HMCs”; this limitation is indefinite, because it is unclear if “HMCs” is a typographical error which should instead be “MSCs,” or instead if HMCs are intended to represent another component.
Claim 24 recites the step of “examining the cerebral spinal fluid of the subject before and after administration”; this limitation is indefinite, because it is unclear what step or steps are intended to be included in, or excluded from, “examining” the cerebral spinal fluid.
Further, claim 24 recites the limitation "the cerebral spinal fluid” in line 2. There is insufficient antecedent basis for this limitation in the claim. No cerebral spinal fluid is previously recited in the claims.
Claims 5, 7, 8, 10, 12, 15, 16, 22, and 23 are included in this rejection as these claims depend from above rejected claims, and fail to remedy the noted deficiencies.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18 indicates the percentage by which the VEGF is decreased, however, claim 17, from which claim 18 depends, indicates that the VEGF concentration is increased. As such, claim 18 fails to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
Claims 2-15, 19, 20, and 22-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Duncan et al. (IDS; Alzheimer’s disease, dementia, and stem cell therapy, Stem Cell Research & Therapy, Vol. 8, No. 111, (2017), pp. 1-9).
With regard to claim 2, Duncan et al. teach methods for treating or inhibiting the progression of Alzheimer’s disease, including teaching human trials that comprise administering a composition comprising a therapeutically effect amount of allogenic MSCs (hUCB-MSCs, hBM-MSCs, hPD-MSCs) to a human subject (Abs.; Table 2).
With regard to claims 3 and 4, Duncan et al. teach obtaining a baseline measurement of biomarkers and cognitive functions of the subject, and then measuring the change in the biomarkers and cognitive function following the period of treatment (Table 2: Outcome measures).
With regard to claims 5, 8, and 13, Duncan et al. teach that the measured biomarkers include Aβ, tau, Th1 and Th2 cytokines (Th2 cytokines are: IL-4, IL-5, IL-9, and IL-13, see Art of Record: Wynn, Abs.), and CSF and blood inflammatory markers (Table 2: Outcome measures), which are inflammation signaling molecules.
With regard to claims 6 and 7, Duncan et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Duncan et al. would necessarily provide the results of: increasing the concentration of cytokines including IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17, sIL-2Rα, and combinations thereof, in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including increasing the cytokine concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%.
With regard to claims 9-12, Duncan et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Duncan et al. would necessarily provide the results of: increasing the concentration of Aβ-38, Aβ-40, Aβ-42, or combinations thereof, in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including increasing the concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%; and decreasing the concentration of tau, phospho-tau, NFL, or combinations thereof, in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including decreasing the concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%.
With regard to claims 14 and 15, Duncan et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Duncan et al. would necessarily provide the results of: decreasing the concentration of pro-BNP and/or TNF-α in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including decreasing the concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%.
With regard to claim 19, Duncan et al. teach performing MRI brain volumetry to establish baseline and post-treatment brain volume ((Table 2; NCT02600130: Outcome measures), which is determining a change in the size of areas in the subject’s brain after administration of the composition comprising allogeneic MSCs.
With regard to claim 20, Duncan et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Duncan et al. would necessarily provide the results of: providing a change in size in areas in the subject’s brain after administration, including the amygdala, cortical nucleus, hippocampus, hippocampal subregions, and/or the corticoamygdaloid transition.
With regard to claims 22 and 23, Duncan et al. teach that the administered composition comprises 2x107 hBM-MSCs and 1x108 hBM-MSCs (Table 2; NCT02600130: Arms (low and high groups)), which are 20x106 MSCs and 100x106 MSCs.
With regard to claim 24, Duncan et al. teach obtaining a baseline measurement of cerebrospinal fluid biomarkers of the subject, and then measuring the change in the CSF biomarkers following the period of treatment (Table 2: Outcome measures), which is examining the CSF of the subject before and after administration of the composition comprising allogenic MSCs.
Claims 2-15 and 19-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al. (IDS; WO 2010/056075, published 2010).
With regard to claim 2, Yang et al. teach a method for treating or inhibiting the progression of Alzheimer’s disease (Abs.; p. 11, line 13-15). The method comprising administering a composition comprising a therapeutically effect amount of allogenic MSCs to a subject (Abs.; p. 12, line 22-24; p. 13, line 7-9).
With regard to claims 3, 5, 8, 13, Yang et al. teach measuring a concentration of biomarkers including IL-4, Aβ42, and tau, which is also deemed to be an inflammation signaling molecule, before and after administration of the composition to a subject having symptoms of Alzheimer’s disease (Fig. 6-11, 13, 19).
With regard to claim 4, Yang et al. teach diagnosing a patient with mild cognitive impairment, which is a symptom of early Alzheimer’s disease, using a neuropsychological test, which is measuring cognitive functions before administration of the composition; then administering the composition comprising MSCs; and finally determining that the progress to Alzheimer’s disease is prevented or delayed in the patient, which is measuring cognitive functions after administration of the composition (p. 11, line 2-15).
With regard to claims 6 and 7, Yang et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Yang et al. would necessarily provide the results of: increasing the concentration of cytokines including IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17, sIL-2Rα, and combinations thereof, in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including increasing the cytokine concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%.
With regard to claims 9-12, Yang et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Yang et al. would necessarily provide the results of: increasing the concentration of Aβ-38, Aβ-40, Aβ-42, or combinations thereof, in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including increasing the concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%; and decreasing the concentration of tau, phospho-tau, NFL, or combinations thereof, in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including decreasing the concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%.
With regard to claims 14 and 15, Yang et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Yang et al. would necessarily provide the results of: decreasing the concentration of pro-BNP or TNF-α, in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including decreasing the concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%.
With regard to claim 19, Yang et al. teach that the length of neurites is significantly increased in a subject after treatment with the MSC composition, as compared to a control (Fig. 11; p. 8, line 4-7), which is determining a change in size of areas in a subject’s brain after administration of the MSC composition.
With regard to claim 20, Yang et al. teach performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as taught by Yang et al. would necessarily provide the results of: changing the size the amygdala, cortical nucleus, hippocampus, hippocampal subregions, and/or corticoamygdaloid transition in the brain of the subject after administration the composition comprising the therapeutically effective amount allogenic MSCs.
With regard to claim 21, Yang et al. teach determination of a change in cortical neurons treated with the MSC-containing composition and a control (Fig. 7), which is determining if a change occurs in the corticoamygdaloid transition of the subject after administration of the composition.
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 2, 16-18, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Duncan et al.
The teachings of Duncan et al. as applied to claim 2 have been set forth above.
With regard to claim 16, Duncan et al. teach that allogeneic human bone marrow-derived MSCs utilized in Trial NCT02833792 express higher levels of angiogenic growth factors including VEGF (p. 6, left col., last para to right col., line 3; Table 2). While it is not specifically taught that VEGF is measured before and after treatment, it would have been obvious to one of ordinary skill in the art to measure VEGF as a biomarker before and after administration of the allogeneic MSCs, as it is known that the administered MSCs express higher levels of VEGF, and biomarkers are already being measured for baseline and post-treatment concentrations in this trial (see Table 2).
With regard to claims 17 and 18, Duncan et al. render obvious performance of the method as claimed, including administration of the components as claimed. As such, performance of the method as rendered obvious by Duncan et al. would necessarily provide the results of: increasing the concentration of VEGF in serum, plasma, cerebral spinal fluid or blood of a subject having Alzheimer’s disease after administration of the composition comprising the therapeutically effective amount allogenic MSCs, including decreasing/increasing the VEGF concentration from 0.5% to 10%, 5% to 10%, 10% to 50%, or greater than 50%.
With regard to claim 21, while it is not specifically taught that the method further includes determining if a change to the corticoamygdaloid transition occurs as a result of administration of the composition, Duncan et al. do teach performing MRI brain volumetry to establish baseline and post-treatment brain volume ((Table 2; NCT02600130: Outcome measures). As such, it would have been obvious one of ordinary skill in the art to determine changes to brain structures known to be affected in subjects with Alzheimer’s disease, including the corticoamygdaloid transition, as can be seen in the present post-treatment MRI.
Claims 2 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al.
The teachings of Yang et al. as applied to claim 2 have been set forth above.
With regard to claims 22 and 23, Yang et al. teach that the dose of the MSCs may range from 1x104 to 1x107 cells/kg (body weight) per day (p. 12. Line 22-24).
As such, a 10 kg subject would be administered 1x105 to 1x108 cells/kg body weight per day, and a 2 kg subject would be administered 2x104 to 2x107 cells/kg body weight per day. It would have been obvious to one of ordinary skill in the art to utilize an amount within the expressly taught range based on the weight of the subject to be treated, including administering 20x106 MSCs to a 2 kg subject and 100x106 MSCs to a 10 kg subject.
With regard to claim 24, Yang et al. teach that the composition may be administered into cerebrospinal fluid (p. 12, line 13-15). As such, it would have been obvious to one of ordinary skill in the art to observe, which is to examine, the cerebrospinal fluid of the subject before and after administration.
Conclusion
No claims are allowable.
Art of Record:
Wynn, Type 2 cytokines: mechanisms and therapeutic strategies, Nature Reviews, Immunology, Vol. 15, (May 2015), pp. 271-282 (Th2 cytokines are: IL-4, IL-5, IL-9, and IL-13).
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/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653