DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
This action is responsive to papers filed 07/28/2026.
Claims 26, 29-30, 36, 39-40, 46, 49-50, 56, 59-60 have been amended.
No claims have been newly added or newly canceled.
Claims 26-30, 36-40, 46-50 and 56-60 are currently pending and have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Interpretation
Independent claims 26, 36, and 56 recite different preambles with regard to the beneficial effect on neural cells of their therapeutic method. Claims 26, 36, 46, and 56 require the administration of conditioned medium from a culture comprising marrow adherent stromal cells that provides trophic factors a-h.
According to MPEP 2111.02, "preamble language merely extolling benefits or features of the claimed invention does not limit the claim scope without clear reliance on those benefits or features as patentably significant" In Poly-America LP v. GSE Lining Tech. Inc., 383 F.3d 1303, 1310, 72 USPQ2d 1685, 1689 (Fed. Cir. 2004).
Previous claims 10 and 20 indicated that the restoration and recruitment of dopaminergic neurons to a site of neural degeneration were provided by a culture of marrow adherent stromal cells that had been encoded a Notch intracellular domain by method steps (a) and (b) that results from the same trophic factors as a-h that are recited in the current claims. Therefore, marrow adherent stromal cells that are cultured as recited in steps (a) and (b) in previous claims 1 and 11 (independent claims of claims 10 and 20), and include the Notch intracellular domain, are deemed to meet the requirements for producing the same trophic factors from the cells and their conditioned culture medium, and thus deemed to provide the same benefits when administered to a subject as recited in the preambles of the current claims.
Providing guidance on instances where the method steps of the prior art and instant claims are the same, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) states “[T]hat since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims.”
Claim Rejections - 35 USC § 112
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.
Claims 26-30, 36-40, 46-50, and 56-60 are 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.
Applicants have entered the limitation “wherein the NICD terminates at amino acid 2504 of the Notch-1 protein” in claims 26, 36, 46 and 56. There is insufficient support in the disclosure as originally filed for this limitation; thus it is being considered new matter. The disclosure as originally filed only supports wherein the Notch intracellular domain consists of amino acids 1703-2504 of the Notch-1 protein (page 3 para 9, page 4 para 17, page 5 para 27, page 6 para 47), but does not disclose any and all amino acids sequences terminating at amino acid 2504.
This amendment to the claims now includes amino acids outside the disclosed range of 1703-2504 and thus includes new matter.
An amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). Applicant is required to cancel the new matter in the reply to this Office Action.
The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir.1996).
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 26-30, 36-40, 46-50 and 56-60 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dezawa et al (US 2006/0166362-from IDS filed 03/14/2024) as evidenced by Tate et al (Cell Transplantation 2010-previously cited) and in view of Messina et al (US 2006/0233765-from IDS filed 03/14/2024), Dezawa et al (hereinafter referred to as “Dezawa 2005”, Expert Opinion on Biological Therapy, 2005-from IDS filed 03/14/2024), Naughton et al (US 6372494-previously cited) and Artavanis-Tsakonas et al (US 2005/0112121-newly cited).
Regarding claims 26-30, 36-40, 46-50 and 56-60, Dezawa et al teach a method for treating neurodegenerative diseases by administering cells which are derived from bone marrow stromal cells (MSCs) into which the Notch gene or Notch signaling related gene had been introduced (contacted)(page 2 para 15 and page 7 para 120). The stromal cells are transfected for the Notch-1 protein starting at amino acid 1703 and terminating at the 3' untranslated sequence (page 10 para 160) which would inherently contain amino acids 1703-2504 of the Notch 1 protein but not the full-length protein. Culturing of the cells is taught (page 4 para 41 -43) and selecting the cells into which the genes have been introduced (page 6 para 98). Introducing these cells into a site of neural degeneration (page 6 para 103-105).
The reference teaches wherein the polynucleotide does not encode the full- length Notch protein (page 3 para 30 and page 11 para 176). Beneficial treatment of patients suffering from a disease or disorder of the central nervous system is taught (page 6 para 103) and includes Parkinson's disease (page 7 para 111) and Alzheimer’s disease (page 7 para 114) which Applicant has indicated are degenerative diseases/disorders that benefit from the claimed treatment method in either the central nervous system or the peripheral nervous system (page 3 para 8 of the as filed specification).
Although the Dezawa reference does not explicitly teach wherein the neural cells provide for the restoration, recruitment, enhanced survival, stimulated growth, enhanced neurite outgrowth, or rescue of damaged neural cells in a subject or provide for trophic factors or the specific manner of repair of the damaged neural tissue, these effects are deemed to be inherently present since the Dezawa method is administering cells that are produced by a method that carries out the same claimed cell production steps with the same claimed cell types (based on Applicant’s previous claims 1-20).
Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims."
Although the Dezawa reference does not explicitly teach wherein the subjects treated require restoration or recruitment of endogenous neurons or glial cells, subjects suffering from Parkinson’s disease and Alzheimer’s disease inherently benefit from these effects and thus must require them to some extent regardless of whether the Dezawa reference acknowledges this or not. Evidence of this benefit is provided by Applicant’s disclosure as well as the teaching of Dezawa.
Additional evidence that adherent stromal cells transfected with NICD inherently provide the claimed trophic factors is demonstrated by Tate (pages 981-982, tables 1 and 2). Tate demonstrate that MSCs transfected with NICD (Notch intracellular domain, SB623 cells) produce trophic factors such as BMP-4, Dkk-1, FGF7, HB-EGF, IL6, MCP1, PDGF-AA, and VEGF (pages 981-982, tables 1 and 2).
Dezawa do not specifically disclose administering conditioned medium of the therapeutic cells to damaged neural tissue.
Messina teach the repair of tissue damaged by neural degenerative disorders using cells that have the potential to differentiate into neural cells and include genetically engineered cells (pages 2-3, para 14-16). Biological products produced by cells and secreted into the medium can be readily isolated from conditioned medium using standard separation techniques (page 11 para 93). Use of the cell conditioned medium allows the beneficial trophic factors secreted by the cells to be used in a patient without introducing intact cells that could trigger a reaction or other adverse response. Conditioned medium is prepared by culturing the cells in a culture medium and then removing the cells from the medium (page 11 para 95-96). Pharmaceutical compositions containing conditioned medium are taught and suggested (page 12 para 103) and include the treatment of patients with damaged neurological tissue, such as in a stroke patient (page 17 para 139).
Dezawa 2005 disclose that the reason why MSC transplantation improved motor function upon transplantation has been explained mainly by the production of trophic substances beneficial for nervous tissue. MSCs also secrete trophic factors effective in neuroprotection, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), hepatocyte growth factor and vascular endothelial growth factor (VEGF) as well as IL-6 (page 428, column 1).
Naughton disclose the use of conditioned culture medium compositions as a pharmaceutical for the treatment of damaged tissue (abstract, column 4 line 40-column 6 line 17). Suitable cell types to use to make the conditioned medium include stromal cells such as mesenchymal stem cells (column 4 lines 46-51, column 6 lines 33-37) and cells engineered to express gene products (column 5 lines 40-45). Cells that secrete trophic factors such as NGF into the conditioned medium are indicated as useful for the treatment of neurodegenerative disorders, specifically injury to a nerve, including the central nervous system (column 24 line 13-column 25 line 12).
One of ordinary skill in the art would have been motivated to administer conditioned medium from the therapeutic cells transfected with sequences encoding NICD to patients in the method of Dezawa because Messina teach and suggest that conditioned medium will contain the therapeutic tropic factors that are secreted by the therapeutic cells during culture and can provide beneficial and therapeutic effects for a patient with a neural degenerative disorder that is treated by therapeutic cells. Dezawa 2005 disclose that MSCs (stromal cells) transplantation is known to provide its therapeutic effect mainly by production of trophic substances beneficial for nervous tissue. MSCs also secrete trophic factors effective in neuroprotection, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), hepatocyte growth factor and vascular endothelial growth factor (VEGF) as well as IL-6 (page 428, column 1). One of ordinary skill in the art would have had a reasonable expectation of success because Naughton teach and suggest that the conditioned medium of cell types such as stromal cells, and specifically MSCs and genetically engineered cells, are known in the art to be beneficially administered for the treatment of damaged tissue, especially cells that are known to secrete trophic factors that repair damaged nerve tissue and Dezawa 2005 indicate that MSCs secrete trophic cells such as NGF that provide neuroprotection.
One of ordinary skill in the art would have had a reasonable expectation of success because Messina indicate that their administered cells are similar to those adult stem cells derived from bone marrow that give rise to neural lineages (pages 1-2, para 10-12) and both Messina and Dezawa indicate that Parkinson’s disease and Alzheimer’s are neurodegenerative diseases that would benefit from administration to the peripheral nervous system as well as the central nervous system.
Dezawa do not specifically disclose wherein the NICD terminates at amino acid 2504 of the Notch-1 protein.
Artavanis-Tsakonas disclose therapeutic methods and compositions based on Notch proteins (Title and abstract) to repair a damaged nervous system (page 2 para 12) and wherein the NICD they use terminates at amino acid 2504 of the Notch protein (page 19 para 208).
One of ordinary skill in the art would have been motivated to use the portion of the NICD that terminates at amino acid 2504 of the Notch-1 protein in the method of Dezawa because Artavanis-Tsakonas teach and suggest that this is a suitable and beneficial NICD sequence for transfection into a cell line. One of ordinary skill in the art would have had additional motivation and a reasonable expectation of success because Artavanis-Tsakonas are also directed to the use of NICD for the treatment of a damaged nervous system.
Regarding claims 30, 40, 50, and 60, Dezawa teach the method as described above, but do not specifically teach wherein the neural degeneration site and site of administration is in the peripheral nervous system.
Messina teach the repair of tissue damaged by neural degenerative disorders using cells that have the potential to differentiate into neural cells and include genetically engineered cells (pages 2-3, para 14-16). The neural degenerative disorders include Parkinson’s disease and Alzheimer’s disease (page 5 para 47). The cells may be administered at a pre-determined site in the central or peripheral nervous system of the patient where they may exert trophic effects on the nervous system of the patient (page 3 para 17). Culture expansion of cells used to treat a neurodegenerative condition is also taught and suggested (page 2 para 13, page 4 para 40).
Therefore, one of ordinary skill in the art would have been motivated to apply the treatment method of Dezawa for administration to damaged sites in the peripheral nervous system because Messina teach that these are sites that would benefit from cells that provide trophic effects and have the capability to differentiate into neural cells. One of ordinary skill in the art would have had a reasonable expectation of success because Messina indicate that their administered cells are similar to those adult stem cells derived from bone marrow that give rise to neural lineages (pages 1-2, para 10-12) and both Messina and Dezawa indicate that Parkinson’s disease and Alzheimer’s are neurodegenerative diseases that would benefit from administration to the peripheral nervous system as well as the central nervous system.
Therefore, the combined teachings of Dezawa et al, Messina et al, Dezawa 2005 and Naughton et al render obvious Applicant’s invention as claimed.
Terminal Disclaimer
The terminal disclaimer filed on 10/03/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US 8,945,919 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Response to Arguments
Applicant's arguments filed 07/28/2026 have been fully considered but they are not persuasive. Applicant’s arguments have been addressed in so far as they relate to the current rejections above.
Applicant argues that their amendment to the claims has overcome the rejection under 35 USC 112 first paragraph and requests that this rejection be withdrawn.
This is not found persuasive. While the amendments have overcome the previous new matter rejection they have done so by incorporating additional limitations that also do not find support in Applicant’s disclosure and thus the new matter rejection remains directed to the new limitations.
Applicant argues that their amendment to the claims has overcome the rejection under 35 USC 103(a) because none of the cited references teaches or suggests a NICD that terminates at amino acid 2504 of the Notch-1 protein.
This is not found persuasive because the previous rejection has been amended to include the teachings of Artavanis-Tsakonas, as described above, which does teach and suggest a NICD that terminates at amino acid 2504 of the Notch protein and this combined with the teachings of Dezawa render obvious the invention as claimed.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ellisen et al., “TAN-l, the Human Homolog of the Drosophila Notch Gene, Is Broken by Chromosomal Translocations in T Lymphoblastic Neoplasms”, Cell, 1991, Vol. 66, pp. 649-661.
(Ellisen disclose the amino acid sequence of the Notch gene)
Wharton et al., “Nucleotide Sequence from the Neurogenic Locus Notch Implies a Gene Product That Shares Homology with Proteins Containing EGF-like Repeats”, Cell, Vol. 43, No. 3, (Part 2), 1985, pp. 567-581.
(Wharton disclose the amino acid sequence of the Notch gene)
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631
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