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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/26/2026 has been entered.
Response to Amendments
Applicant's amendments filed 5/26/2026 to claims 1, 17, 22, 24, 32, 35, and 38 have been entered. Claims 5, 7, 8, 12-16, 18, 23, 26, 28-31, 33, 34, 36, and 37 have been canceled. Claims 1-4, 6, 9, 10, 11, 17, 19, 20, 22, 24, 25, 27, 32, 35, and 38 remain pending, and are being considered on their merits. No claims are withdrawn from consideration at this time. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
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.
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.
Claims 1, 2, 4, 9, 17, 22, 25, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Stem Cells (2010), 28:1099-1106; provided in the IDS dated 11/19/2021) in view of Shelton et al. (Stroke. 2001;32:107-112) as evidenced by Gu et al. (Journal of Stroke and Cerebrovascular Diseases (2014), 23(10), pp2598-2506), Kolf et al. (Arthritis Research & Therapy (2007), 9(207), 10 pages), and Kim et al. (Stem Cells Dev (2012), 21(16), 2958-2968).
Lee teaches a method of reducing infarct volume in human subjects following an ischemic stroke (i.e. cerebral infarction, stroke in the cerebral cortex), the method comprising 1) obtaining and culturing autologous/autogeneic mesenchymal stem cells obtained from bone marrow, and 2) intravenously administering a therapeutic effective dosage of the cultured MSCs to the subjects such as to increase patient survival (“Study Design” and “Patient Enrollment and Randomization” on p1100 for subjects; “Preparation and Transplantation of MSCs” on p1100-1101 for MSC administration; Fig. 2 for patient outcome), reading on claims 1, 16, 17, 22, and 25. Lee teaches 52 patients in the treatment group suffering from acute ischemic stroke (1st paragraph of the Results on p1101-1102), reading on claim 2. Lee teaches 2 subjects in the treatment group suffering having intra-infarct hemorrhage (Table 1), reading on claim 4. Lee teaches more subjects in the treated group had an improvement in the modified Rankin Scale score (e.g. a negative rank) (p1103, subheading “Functional Outcomes”), reading on the embodiment of an improved mRS score for improved motor function for claims 1 and 9. Lee teaches expanding the human mesenchymal stem cells prior to administration (“Preparation and Transplantation of MSCs” on p1100-1101), reading on claim 21. Lee teaches administering two dosages of autologous human mesenchymal stem cells to the subjects (“Preparation and Transplantation of MSCs” on p1100-1101), reading on claim 32.
Regarding claim 1, Lee is silent if the bone marrow-derived mesenchymal stem cells are STRO-1+ and TNAP+. However, Kolf teaches that bone marrow-derived mesenchymal stem cells are defined as being STRO-1+ (see Table 1 and pages 6-7, 1st paragraph under “Cellular components”). Similarly, Kim teaches that bone marrow-derived mesenchymal stem cells inherently comprise a population of cells that are TNAP+ (see the Abstract). Therefore and absent any showing to the contrary, the bone marrow-derived mesenchymal stem cells of Lee are substantially identical to the claimed mesenchymal stem cells and so are reasonably presumed inherently STRO-1+ and TNAP+ as claimed and so Lee as evidenced by Kolf and Kim reads on claim 1. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established, and Applicant has the burden of showing they are not; see M.P.E.P. § 2112.01
Regarding claim 1, Lee and Shelton do not teach subjects having cerebral infarction in the motor cortex.
Shelton teaches human subject having suffered from ischemic stroke and having minimal upper limb movement, lesions were detected in the motor cortex (Abstract), reading on claim 1.
Regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the subjects of Lee for the subjects of Shelton in Lee’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and Shelton are in-part directed towards similar populations of human subjects suffering and having neurologic symptoms from ischemic stroke The skilled artisan would have been motivated to do so because the substitution would be predictably advantageous to improve the survival of the subjects Shelton.
Regarding claim 1, Lee is silent if there is an increased in cortical activation in the infarct volume of the treated subjects. However, Gu teaches that when human mesenchymal stem cells are administered to mammalian subjects suffering from cerebral ischemia (e.g. stroke, stroke in the cerebral cortex), the mesenchymal stem cells persist in the infarcted area (paragraph spanning both columns on page 2600), that reduces inhibits/reduces apoptosis (e.g. programmed cell death) as measured by the protein expression of relevant apoptotic markers (Abstract and the 1st paragraph on page 2600 and Fig. 4). Gu further teaches that apoptotic cell death is an important pathophysiologic mode of cell death in ischemic brain injury (the paragraph staring “A wealth of evidence…” on page 2602). Therefore and absent any showing to the contrary, the methods of Lee and Shelton are reasonably presumed to be inherently capable of meeting the embodiment of claim 1 wherein cortical activation is increased in the infarct volume by decreasing endogenous apoptosis, and so Lee as evidenced by Gu reads on claim 1; see M.P.E.P. § 2112.
Alternatively regarding claim 1, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See M.P.E.P. § 2111.02 and 2111.04. In case, claim 1 recites “wherein the cerebral infarction is in the cortex and wherein cortical activation is increased within the volume of the infarct following administration.” which is simply a statement of intended result outcome of the claimed method and so is afforded no patentable weight.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of van Velthoven et al. (Journal of Neuroscience (2010), 30(28), 9603-9611).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 3, Lee and Shelton do not teach treating subjects having hypoxic ischemic encephalopathy (i.e. HIE).
van Velthoven teaches that that a single bone marrow-derived mesenchymal stem cell treatment at three days after neonatal hypoxia–ischemia (HI) in postnatal mammalian subjects improved sensorimotor function and reduced lesion size (Abstract; Fig. 1 and detailed methods on p9604-9605), reading on claim 3. van Velthoven teaches that perinatal cerebral hypoxia–ischemia (HI) remains a major cause of neonatal morbidity and mortality, for which there are limited treatment options (the 1st paragraph of the Introduction on p9603), reading on claim 3.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the subjects suffering from stroke, the subject population being a mix of ischemic and hemorrhage lesions in Lee’s methods with human subjects suffering from perinatal cerebral hypoxia-ischemia (e.g. HIE) in view of van Velthoven. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and van Velthoven are directed towards bone marrow-derived mesenchymal stem cells and associated methods of treating subjects suffering from ischemic disease, and because van Velthoven teaches operable methods of treating neonatal hypoxia–ischemia in an art-accepted animal model. The skilled artisan would have been motivated to do so because van Velthoven teaches that that perinatal cerebral hypoxia–ischemia (HI) remains a major cause of neonatal morbidity and mortality, for which there are limited treatment options, and so the substitution would be predictably advantageous to then treat human subjects suffering from suffering from perinatal cerebral hypoxia-ischemia in the methods of Lee.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Sugimori et al. (Neuroscience Letters 300 (2001), 13-16).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 6, Lee and Shelton do not teach an reduction in the cerebral infarction volume after mesenchymal stem cell administration.
Sugimori teaches that intravenous administration of 50 µg/kg per hour of basic fibroblast growth factor (bFGF) in mammalian subjects having suffered from ischemic stroke reduces infarct volume by about 27% at three months post-infarction (Abstract), reading on claim 6. Sugimori teaches that bFGF crosses the blood-brain barrier and exerts direct cytoprotective effects by downregulating the protein Bcl-2 as a known apoptotic protein (paragraph starting “Basic fibroblast growth factor…” on page 13), reading on claim 6.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the bFGF administration methods of Sugimori to the mesenchymal stem cell administration methods of Lee. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and Sugimori are both in-part directed towards treating mammalian subjects having suffered from ischemic stroke and because Sugimori teaches a specific dosage of bFGF. The skilled artisan would have been motivated to do so because Sugimori teaches that intravenous administration of 50 µg/kg per hour of basic fibroblast growth factor (bFGF) in mammalian subjects having suffered from ischemic stroke reduces infarct volume by about 27% at three months post-infarction, and so the combination would likely improve the methods of Lee in treating human subjects having suffered from ischemic stroke by reducing the infarct volume and thus reduce cellular apoptosis and amount of damaged cortical tissue in Lee’s subjects.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Jang et al. (Journal of Biomedicine and Biotechnology (2011), Article ID 238409, 11 pages).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 10, Lee and Shelton do not teach cortical activation in response to contralateral tactile stimulation.
Jang teaches methods of administering bone marrow-derived mesenchymal stem cells to rodent subjects having suffered from ischemic stroke (Abstract). Jang teaches assaying motor function in the rodents by the adhesive removal test, wherein two small adhesive paper dots are applied to the forelimb wrists as bilateral stimuli and the time to remove the paper dots is measured (paragraph starting “Adhesive-Removal Test” on pages 4-5), reading in-part on claim 10. Jang teaches that for rodents suffering from ischemic stroke and having been administering mesenchymal stem cells had superior scores in the adhesive removal test as compared to control rodent subjects (subheading 3.2 on page 6), reading on claim 10. Jang teaches that the adhesive removal test is indicative of motor function of the forelimbs whereas the treadmill test is indicative of motor function of the all limbs in rodents (paragraph starting “In our study…” on page 10), reading on claim 10.
Regarding claim 10, it would have been obvious to a person of ordinary skill in the art before the invention was filed to treat the human subjects of Lee such as to improve cortical activation as measured by contralateral tactile stimulation in view of Jang. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and Jang are directed towards mammalian subjects, and while Jiang teaches specific methods of measuring tactile stimulation in rodents Jang also provides a reasonable expectation of success that human subjects treated with mesenchymal stem cells would improve cortical activation as measured by a tactile stimulation. The skilled artisan would have been motivated to do so tactile and contralateral tactile stimulation would otherwise be a non-invasive method of assaying the subjects of Lee for motor deficits caused by the ischemic stroke suffered by said subjects.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Honmou et al. (US 7,968,088).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 11, Lee and Shelton do not teach systemic administration of the mesenchymal stem cells at about 24 hours or less, or at about 12 hours or less, following the cerebral infarction.
Honmou teaches methods of administering human or murine bone marrow-derived mesenchymal stem cells to rats suffering from cerebral infarction (Abstract). Honmou teaches the treatment for stroke can be less than 24 hours, less than 12 hours, or less than 6 hours after the occurrence (Col. 7, lines 47-52), reading on claim 11. Honmou teaches that the degree of the therapeutic effect of mesenchymal stem cell administration of cerebral infarction in the rat subjects is more prominent the earlier that the cell transplant is conducted (Example 16 and Figure 18), reading on claim 11.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to treat the subjects of less than 24 hours, less than 12 hours, or less than 6 hours after the occurrence of cerebral infarction in Lee’s subjects in view of Honmou. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and Honmou are directed towards the administration of mesenchymal stem cells to mammalian subjects to treat cerebral infarction. The skilled artisan would have been motivated to do so because Honmou teaches that the therapeutic effect of the mesenchymal stem cell administration is more effective when administered earlier relative to the occurrence of cerebral infarction, and so the earlier treatment intervention of Honmou would then predictably improve upon the methods of Lee by improving the therapeutic effect of the mesenchymal stem cell administration in Lee’s methods.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claims 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Steinburg et al. (Stroke. 2016;47:1817-1824).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 19, Lee and Shelton do not teach administering about 2 x 106-7 mesenchymal stem cells/cm3 of affected cortex. Regarding claim 20, Lee and Shelton do not teach administering 0.1-5 x 106 mesenchymal stem cells/kg body weight of the subjects.
Steinburg teaches methods of administering allogeneic human bone marrow-derived mesenchymal stem cells expressing transgenic human Notch-1 to subjects in need of treatment for stroke (i.e. SB623 cells; Abstract and subheading “SB623 Cells” on page 1818, also Table 1 noting the subjects having infarct(s)). Steinburg teaches administering a single dose of 2.5 x 106, 5.0 x 106, or 10 x 106 SB623 cells (subheading “Study Design, Dosing, and Administration” on page 1818) and that the subjects showed an improvement in clinical outcome endpoints for pooled SB623 cell administration (i.e. all three doses pooled together for evaluation) (Figure 1 and subheading “Clinical Outcome Evaluations”), reading in-part on claims 19 and 20.
Regarding claims 19 and 20, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, the Steinburg teaches that pooled dosages of allogeneic human bone marrow-derived mesenchymal stem cells are effective to treat human subjects having suffered a stroke (e.g. cerebral infarction) as measured by improvements in known clinical outcomes. Similarly, Lee teaches a therapeutic effective dosage of autologous/autogeneic mesenchymal stem cells obtained from bone marrow to the subjects such as to increase patient survival in said patients having suffered from cerebral infarction. While neither Lee nor Steinburg calculate their mesenchymal stem cell dose(s) as cells per cm3 of affected cortex for claim 19 or as cells per kg of subject body weight for claim 20, the teachings of Lee and Steinburg as a whole make clear that the mesenchymal stem cell dose is a known result effective variable to effectively treat subjects in need thereof for cerebral infarction. Thus, the burden is shifted back to establish criticality of the claimed cell concentration ranges of claims 19 and 20 by objective evidence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Steinburg et al. (Stroke. 2016;47:1817-1824) and Honmou et al. (US 7,968,088).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 24, Lee and Shelton do not teach a genetically modified human cell population.
Steinburg teaches methods of administering allogeneic human bone marrow-derived mesenchymal stem cells expressing transgenic human Notch-1 to subjects in need of treatment for stroke (i.e. SB623 cells; Abstract and subheading “SB623 Cells” on page 1818, also Table 1 noting the subjects having infarct(s)), reading on claim 24. Steinburg teaches that the SB623 cells transfected with Notch-1 causes temporary changes in DNA methylation and protein expression such as to (1) secrete factors that protect cells from hypoxic injury, (2) secrete trophic factors that support damaged cells, (3) secrete extracellular matrix proteins that support neural cell growth, (4) have anti-inflammatory effects, (5) have immunosuppressive effects, (6) promote angiogenesis, (7) promote neuronal stem cell migration and differentiation, and (8) provide a biobridge of extracellular matrix metalloproteinases and are advantageous to achieve persistent neurologic recovery by the secretion of supportive molecules rather than by the integration of the transplanted stem cells (subheading “Survival of SB623 Cells” on pages 1823), reading on claim 24.
Honmou teaches methods of administering human or murine bone marrow-derived mesenchymal stem cells to rats suffering from cerebral infarction (Abstract). Honmou teaches the treatment for stroke can be less than 24 hours, less than 12 hours, or less than 6 hours after the occurrence (Col. 7, lines 47-52), reading in-part on claim 24 Honmou teaches that the degree of the therapeutic effect of mesenchymal stem cell administration of cerebral infarction in the rat subjects is more prominent the earlier that the cell transplant is conducted (Example 16 and Figure 18), reading in-part on claim 24
Regarding claim 24, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the autologous human mesenchymal stem cells of Lee with the allogeneic human bone marrow-derived mesenchymal stem cells expressing transgenic human Notch-1 of Steinburg in Lee’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and Steinburg are directed towards methods of administering human mesenchymal stem cells to human subjects for the treatment of cerebral infarction (e.g. stroke). The skilled artisan would have been motivated to do so because Honmou teaches that the degree of the therapeutic effect of mesenchymal stem cell administration of cerebral infarction in the rat subjects is more prominent the earlier that the cell transplant is conducted, and so the SB623 cell line of Steinburg would be predictably advantageous as a preexisting or “off the shelf” mesenchymal stem cell line maintained in cell culture and reduce the time between the occurrence of cerebral infarction in the subjects and the therapeutic administration of mesenchymal stem cells to said subject.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Tajiri et al. (Cell Transplantation, Vol. 25, pp. 1453–1460, 2016).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 27, Lee and Shelton do not teach further comprising administering mannitol.
Tajiri teaches that in a rodent model of experimental stroke, administration of a combination of mannitol human umbilical cord stem cells significantly improves motor performance and brain cell survival in the peri-infarct area compared to rodent subjects that received vehicle or mannitol alone (Abstract and Figure 1), reading on claim 27. Tajiri teaches administering a dose of 1.1 mol/L of mannitol (subheading “HUCBC Transplantation” on p1454)
It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the mannitol or Tajiri and the mannitol dosage taught by Tajiri to the methods of Lee. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and Tajiri are directed towards treating mammalian subjects suffering from stroke by administering human mesenchymal stem cells. The skilled artisan would have been motivated to do so because Tajiri teaches that the combination of mannitol and mesenchymal stem cells improves motor performance and brain cell survival in the peri-infarct area compared to rodent subjects that received vehicle or mannitol alone and so the addition would therefore predictably improve upon the methods of Lee.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Shyu et al. (Stroke. 2007;38:367-374).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 35, Lee and Shelton do not teach labeled human mesenchymal stem cells capable of being detected in vivo.
Shyu teaches methods of tracking administered human mesenchymal stem cells in ischemic rat brain, the method comprising transfecting the mesenchymal stem cells with a MRI contrast agent (i.e. Gd-DPTA) into the mesenchymal stem cells and then administering the transfected mesenchymal stem cells to the subjects (Abstract; Materials and Methods on pages 367-368), reading on claim 35. Shyu teaches that the Gd-DPTA-loaded mesenchymal stem cells are trackable by MRI after administration to the subjects (Figure 2), reading on claim 35. Shyu teaches there is a need in this art for specific methods are needed to continuously and noninvasively monitor stem cell survival because of the potentially broad application of stem cell-based therapies (paragraph starting “Stem cells have been used…” on page 367), reading on claim 35. Shyu teaches that the Gd-DPTA loaded and mesenchymal stem cells were observed differentiating into neuronal cells (Abstract), reading on claim 35.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to further transfect the human mesenchymal stem cells of Lee with Gd-DPTA as an MRI contrast agent in view of Shyu. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Shyu teaches detailed methods of transfecting the human mesenchymal stem cells and further imaging the transfected human mesenchymal stem cells in mammalian subjects, and because both Lee and Shyu are in-part directed towards methods of treating mammalian subjects suffering from stroke by administration of human mesenchymal stem cells. The skilled artisan would have been motivated to do so because teaches there is a need in this art for specific methods are needed to continuously and noninvasively monitor stem cell survival because of the potentially broad application of stem cell-based therapies, and so the further addition of the MRI contrast agent of Shyu would predictably improve upon the methods of Lee by adding the capacity to track Lee’s mesenchymal stem cells in vivo and after administration to the subjects in need of treatment thereof.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim as applied to claim 1 above, and further in view of Ghosh (US 9,888,679).
The teachings of Lee and Shelton and as evidenced by Gu, Kolf, and Kim are relied upon as set forth above.
Regarding claim 38, Lee and Shelton do not teach isolating STRO-1+ and TNAP+ multipotential stem cells with a STRO-3 antibody.
Ghosh teaches that the STRO-3 antibody binds to TNAP (Col. 27, lines 19-28), reading on claim 38. Ghosh teaches methods of isolating STRO-1+ and TNAP+ multipotential cells from bone marrow using magnetic beads labeled with the STRO-3 antibody (Col. 28, lines 25-30), reading on claim 38.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the Ficoll density gradient isolation methods of Lee with the STRO-3 antibody and methods of Ghosh to isolate the STRO-1+ and TNAP+ mesenchymal/multipotential cells of Lee. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lee and Ghosh are both directed towards methods of isolating and obtaining STRO-1 and TNAP+ mesenchymal stem cells. The skilled artisan would have been motivated to do so because Kim and Ghosh teach that bone marrow-derived mesenchymal stem cells are TNAP+ and because Ghosh teaches that the STRO-3 antibody specifically binds TNAP+. Therefore, the substitution would predictably enhance the methods of Lee because the STRO-3 antibody would specifically bind to and isolate the bone marrow-derived mesenchymal stem cells in Lee’s methods as opposed to the Ficoll density gradient methods of Lee.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 5-22 of the reply have been fully considered with respect to the modified grounds of rejection above, but not found persuasive of error for the reasons given below.
On page 7-9 and 11-13 of the reply, Applicant alleges that the examiner has not met the required burden to establish inherency in the obviousness rejection of record. Regarding the STRO-1+ and SNAP+ multipotent stem cells of claim 1, this is not found persuasive of error because when claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established, and the applicant has the burden of showing that they are not; see M.P.E.P. § 2112.01. At this time, Applicant has not shown by any preponderance of evidence that Lee’s bone marrow-derived mesenchymal stem cells are not STRO+ and SNAP+ as evidenced by Kolf and Kim. Regarding the cortical activation of claim 1, Applicant has not shown by any preponderance of evidence to rebut the examiner’s rational that Lee’s bone marrow-derived mesenchymal stem cells would reasonably increase cortical activation by reducing endogenous cell apoptosis as evidenced by Gu; see M.P.E.P. § 2112. And none of Applicant’s arguments address the alternative rational of record that “increase cortical activation” is merely a statement of intended result and so is afforded no patentable weight; see M.P.E.P. § 2111.02 and 2111.04.
In response to applicant's argument on page 9-10 of the reply that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., all MSCs must express STRO-1+) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Claim 1 is generic to the multipotent stem cells and any particular degree of the claimed cells that are or are not STRO-1+, and so Applicant’s arguments are not reasonably commensurate to the broadest reasonable interpretation of the scope of the claims.
On pages 10-11 of the reply, Applicant alleges that there would be no reasonable expectation of success to combine Shelton with Lee. This is not found persuasive of error because a prima facie case does not require absolute predictability (see M.P.E.P. § 2143.02), and Applicants arguments appear to ignore that Lee teaches improvements in motor function in the treated subjects (i.e. administered an effective dosage of the MSCs).
In response to applicant’s argument on page 11 of the reply that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicant’s arguments that there is no motivation to combine Shelton with Lee is not persuasive because the assertion amounts to a general allegation and does not address the specific rationale of record set forth above.
On pages 13-21 of the reply Applicants rely on arguments traversing the above rejection of claim over Lee in view of Shelton and as evidenced by Gu, Kolf, and Kim to traverse the rejections of 1) claim 3 further in view of van Velthoven, 2) claim 6 further in view of Sugimori, 3) claim 10 further in view of Jang, 4) claim 11 further in view of Honmou, 5) claims 19 and 20 further in view of Steinburg, 6) claim 24 further in view of Steinburg and Honmou, 7) claim 27 further in view of Tajiri, 8) claim 35 further in view of Shyu, and 9) claim 38 further in view of Ghosh. Therefore, the response set forth above to the arguments over claim 1 also applies to these rejections.
Conclusion
No claims are allowed. No claims are free of the art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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