DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-8, 10-14, 16-18, and 28-31 were previously pending.
Receipt is acknowledged of the response to restriction submitted on 17 February, 2026. Applicant's election with traverse of the invention of group I (claims 1-8, 10-14, 16-18, and 28-30 in the reply filed on 17 February, 2026 is acknowledged. The traversal is on the ground that the inventions can be reasonably searched together. This is not found persuasive because the instantly filed application was filed under 37 CFR 371. As stated in 1893.03(d), unity of invention (not restriction) practice is applicable in such cases. Search burden is not a criteria in 371 cases.
The requirement is still deemed proper and is therefore made FINAL.
Claim 31 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1-8, 10-14, 16-18, and 28-30 are pending and under examination in the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2022/004342, filed 28 January, 2022, which claims priority to Japan Application Nos. JP2021-013667 and JP2021-167913, filed 29 January, 2021, and 13 October, 2021 respectively. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified untranslated copies of papers required by 37 CFR 1.55 have been filed in this application on 21 July, 2023.
The earliest possible priority for the instant application is 21 July, 2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08 August, 2025, 08 December, 2025, and 13 March, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because FIGs. 1, 6, and 7 are out of focus to an extent which renders them illegible. In addition, FIGs. 3, 4, 5, 6, 10, 11, 12, 16, 17, 18, and 19 were not converted to a form readable by grey-scale and, consequently, lines/bars cannot be effectively distinguished from one another in accordance with the figure legends. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Applicant is advised that should claim 1 be found allowable, claims 2 and 17 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claims 4, 5, and 11 are objected to because of the following informalities: abbreviations/acronyms need to be spelled out upon their first encounter in the claims (for example: LNGFR, Thy-1, GPC-MALS). Appropriate correction is required.
Examiner Comment
Throughout the present Official Action, where reference is made to the instant Specification, the Examiner will be referring to the publication of the instant Application for ease of citation (US20240100099).
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 3-8, 10, 13, and 17 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.
The term “high-purity” in claims 3, 4, and 5 is a relative term which renders the claim indefinite. The term “high-purity” 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. Neither the claim nor the specification defines how pure MSCs must be to be considered “high-purity”. The specification contains a definitions section which does not in itself define “high-purity” and nowhere else in the specification is such a limiting definition presented. Therefore, the term is relative and a person having ordinary skill in the art would not be apprised of the scope of claims 3-5.
The term “rapidly proliferating” in claims 4 and 5 is a relative term which renders the claim indefinite. The term “rapidly proliferating” 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. Neither the claim nor the specification defines how rapid MSCs must proliferate to be considered “rapidly proliferating”. The specification contains a definitions section which does not in itself define “rapidly proliferating” and nowhere else in the specification is such a limiting definition presented. Therefore, the term is relative and a person having ordinary skill in the art would not be apprised of the scope of claims 4-5.
Claim 6 is unclear in its recitation of “the intervertebral disc of a subject in need thereof and-which has fluidity upon the application thereof”. It is unclear whether Applicant intends the human subject to have “fluidity” or the intervertebral disc to have “fluidity”. It is further unclear what comprises “fluidity” in these contexts as both of these terms are not typically referred to as having fluidity. Accordingly, the metes and bounds of claim 6 are unclear and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claims 7-8 are further rejected for their dependency on a rejected base claim.
The term “low” in claim 10 is a relative term which renders the claim indefinite. The term “low” 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. Neither the claims nor the specification describe how low the concentration of endotoxin has to be in the monovalent metal salt of alginic acid to be considered “low endotoxin”. Accordingly, the metes and bounds of claim 10 are unclear and a person having ordinary skill in the art would not be apprised of the scope of the claim.
Claim 13 recites “wherein the application of the composition is effective for reducing intervertebral disc degeneration”. “Reducing” is a relative term which renders the claim indefinite. Neither the claim nor the specification defines “effective for reducing intervertebral disc degeneration” and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought. Specifically, a person having ordinary skill in the art would not know how to assess the relative effectiveness nor how much degeneration would have to be reduced in order to be effective and to fall within the scope of the claimed invention.
Claim 17 recites the limitation "wherein regeneration of the nucleus pulposus cells is" in the second line of the claim. There is insufficient antecedent basis for this limitation in the claim. Neither claim 17 nor claim 2 from which claim 17 depends recites “regeneration of the nucleus pulposus cells”. In fact, claim 2 was amended to remove this language. Accordingly, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
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 1-8, 10-14, 16-18, and 28-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of treating intervertebral disc degeneration, comprising: (i) injecting a liquid composition comprising a monovalent metal salt of alginic acid and mesenchymal stem cells into a nucleus pulposus of a damaged intervertebral disc; and (ii) spraying a solution of 102 mM CaCl2 onto the liquid composition, wherein the spraying of the solution of 102 mM CaCl2 induces gelation of the liquid composition, and wherein the composition comprises 2% weight volume of the monovalent metal salt of alginic acid and 1 x 106 mesenchymal stem cells per mL of the composition,
does not reasonably provide enablement for a method of treating any intervertebral disc comprising applying by any mechanism and in any form a composition comprising any amount of a monovalent metal salt of alginic acid and any amount of mesenchymal stem cells to the intervertebral disc of any subject in need thereof (reading on a method of prevention). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims 1-8, 10-14, 16-18, and 28-30 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.
While the written description and enablement requirements are separate and generally separable requirements, the instant application fails to meet either requirement for reasons which overlap significantly, as set forth below.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of the Invention. The claims are drawn to a method of treating an intervertebral disc in a subject in need thereof comprising applying a composition wherein the composition comprises a monovalent metal salt of alginic acid and mesenchymal stem cells (MSCs).
2) Scope of the Invention. The scope of the instant invention is quite broad. A method of treating can broadly encompass any end-state which can be considered to treat a disease state while the claims themselves do not even require a disease state and instead just require that a subject be “in need thereof”. The claims also broadly read on any mechanism of application (implantation, injection to the exterior of the vertebrae, placed onto or sprayed at an exposed spine) of any form of the composition (liquid, solid, gaseous). The claims as recited read on a broad genus of methods in which gelation of the composition isn’t even required (raising issues of adequate written description as well as enablement). The claims also read on a composition having any amount of mesenchymal stem cells having the function of “treating an intervertebral disc” (raising issues of adequate written description as well as enablement) and any amount of alginic acid.
3) Number of Working Example and Guidance. The specification teaches several in vivo examples for the application of a composition to an intervertebral disc. The specification teaches the generation of an intervertebral disc (IVD) annulus fibrosis puncture rabbit model and the transplantation of a 2% (w/v) ultra-purified alginate (UPAL) solution containing BMSCs into a defect site in the nucleus pulposus of said models where the defect site was manually created by excising the nucleus pulposus ([0407]-[0409]). This example does not teach how many cells were in the UPAL but the specification teaches separately UPAL loaded with 1 x 106 BMSCs per mL of solution with an additional 1 x 106 nucleus pulposus cells per mL of solution ([0401]). Importantly, the specification teaches that 1mL of 102mM CaCl2 needed to be sprayed on top of the UPAL immediately after transplantation to induce gelling of the composition ([0409]). The specification teaches that the method in the rabbits resulted in increased collagen type II expression, and decreased type I collagen expression in the intervertebral disc ([0426]-[0427]). The specification also teaches the application of the method to sheep (Example 3). The specification is much more concise with regard to the method for sheep and merely states that BMSCs “suspended in UPAL at a final concentration of 1 x 106 cell/ml (100μl) were then injected into the voids in the intervertebral discs” ([0518]). Although this example does not specify the requirement for gelation, it is presumed to be a necessary step owing to the next Example in which sheep had 110 to 120 μL of a 2% UPAL solution containing 1 x 106 cell/ml of BMSCs transplanted into voids in their intervertebral discs immediately followed by injecting a 102 mM solution of CaCl2 onto the surface of the UPAL mixture ([0559]). The working examples again teach an increase in type II collagen expression and a decrease in type I collagen expression as the result of the method in sheep ([0593]). In the final working example, an identical method is performed on rats except the goal was to read out relative pain in the treated and untreated groups (Example 5). Notably, while the example in rats purports to show “a pain-suppressing effect”, no figures have been submitted in connection with the rat example to exemplify the findings of the three tests used to assess pain ([0672]). While the example describes what each of the three tests are, it stops short of teaching the results and instead just says that the data is “shown” without actually showing it ([0668]-[0671]). No example is provided in which a composition other than a 2% (w/v) UPAL solution containing 1 x 106 cell/ml of BMSCs is applied to an intervertebral disc in any manner other than via injection into the nucleus pulposus. No example is provided in which a composition is injected in any form other than as a liquid wherein gelation is induced by spraying a solution of CaCl2 onto the composition after transplanting. No example is provided in which any cells other than BMSCs were used. In addition, no example is provided in which any subject “in need thereof” is treated at all other than subjects in which their nucleus pulposus was excised and the result of transplantation was an increase in type II collagen expression with decreased type I collagen expression.
4) State of the Art. The state of the art for BMSC transplantation as a treatment for intervertebral disc degeneration goes as far back as 2006 (See Zhang, et al., Stem cell research & therapy 13.1 (2022): 70, hereinafter “Zhang”; See also Sakai, et al., " Biomaterials 27.3 (2006): 335-345, hereinafter “Sakai”). Zhang teaches the mechanism of intervertebral disc degeneration as involving a gradual degeneration of the nucleus pulposus cavity (Zhang, Fig. 1). Zhang also teaches various characteristics of different stem cell types that could be used to treat such a degeneration (Zhang, Table 1). With regard to in vivo application of stem cells to treat intervertebral disc degeneration, Zhang teaches autologous BMSCs transplanted into a rabbit model citing to Sakai as well as sheep, rat, and bovine models (Zhang, page 5, last partial paragraph; Table 3). Zhang also teaches that this technology has made the leap into human clinical trials (Zhang, page 6, first full paragraph). In this context, BMSCs were injected into the nucleus pulposus of human patients with varying success (Zhang, page 6, first full paragraph). Zhang also teaches that other MSC types like adipose-derived and umbilical cord MSCs have similarly been used in clinical trials with varying effectiveness (Zhang, Table 8). Thus, the injection of MSCs into the nucleus pulposus of intervertebral discs as a method of treating intervertebral disc degeneration is not new and the state of the art is only established with respect to treating already damaged discs rather than with respect to preventing the damage in the first place.
5) Unpredictability of the Art. The art at the time of filing evidences unpredictability with respect to the use of alginate solutions of any concentration of alginate to treat intervertebral discs without the induction of gelation (See Bron, et al., Journal of the mechanical behavior of biomedical materials 4.7 (2011): 1196-1205, hereinafter "Bron"). Bron teaches that Alginate is frequently studied as a scaffold for intervertebral disc repair because it closely mimics the mechanical properties of the nucleus pulposus (Bron, Abstract). Bron also teaches that conditions like gelation temperature, type of crosslinker, and alginate concentration all influence the final mechanical properties of alginate scaffolds (Bron, page 1197, second full paragraph). Bron also teaches two types of gelation (both of which use calcium) wherein one is the diffusion method relied upon in the instant Application with some modifications (Bron, page 1197, last paragraph; page 1198, first paragraph). Bron teaches that 2% alginate scaffolds gelled by diffusion of Ca2+ diffusion most closely resembled the mechanical properties of a healthy nucleus pulposus around 11 kPa and that varying the concentration of alginate can vary the final kPa over 2 orders of magnitude in a relatively small range of concentrations (from 1 kPa to 100 kPa) (Bron, page 1201, “Discussion”). Thus, the skilled artisan at the time of filing knew that not just any concentration of alginic acid could be used to produce a scaffold for the treatment of an intervertebral disc with a defective nucleus pulposus and that gelation is required to produce the mechanical properties that most closely resemble a healthy nucleus pulposus.
The ”in need thereof” language in the claims encompasses subjects in which a disease state has not yet been established. Thus, as written, the claims encompass methods of prevention. This requires predicting the subjects that would require treatment which would be highly unpredictable. In humans, the claimed diseases are usually established before therapy is offered. The specification does not adequately teach how to effectively predict for whom prevention would be required. One establishes a large genus of target subjects for whom the method is intended, however, establishing whether a person or persons actually requires the treatment is a highly unpredictable art. Screening procedures for indications of those requiring inhibition of the onset of disease are unknown and highly prejudicial leading to conditions in which those who require the treatment cannot be distinguished from those who do not. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, applicants exacerbate the unpredictability of the art by reciting subjects to be targeted for whom the disease must be prevented.
This raises issues under description as well as enablement. The description component of the rejection is herein included as you cannot use what you have not described. The enablement of the instant invention has been assessed in light of the specification and the prior art available at the time of filing. "However, claims reading on significant numbers of inoperative embodiments would render claims non-enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative. Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298,302 (CCPA 1971). (see MPEP 2164.08(b). Specifically, the claims read on a method of applying an alginate scaffold to an intervertebral disc in which gelation is not required and any amount of mesenchymal stem cells and any amount of alginic acid can be used. The skilled artisan, upon viewing the specification would conclude that the inventors here specifically injected a solution containing 1 x 106 BMSCs/ml and 2% (w/v) alginic acid into a damaged nucleus pulposus, then sprayed a 102mM CaCl2 solution on the alginate liquid to induce gelation. No other concentrations of BMSCs, no other concentrations of alginic acid, and no other method other than one including a gelation step was shown to have the effects of increased type II collagen expression and decreased type I collagen expression that Applicants and the art identify as being treating for damaged intervertebral discs. Thus, the genus claimed encompasses a significant number of inoperative embodiments in its encompassing any amount of mesenchymal stem cells, any amount of alginic acid, applies in any way, and not including a gelation step, having the function of “treating”.
Thus, the skilled artisan at the time of filing, upon viewing the supporting disclosure would not have concluded that the inventors were in possession of the genus of methods currently claimed.
6) Amount of Experimentation Required. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention.
Consequently, the art at the time of filing when combined with the lack of any disclosed direct experimental test of a method other than the specific method disclosed by Applicant and discussed above, shows that one of skill in the art at the time the invention was made would have had no basis to reasonably predict or conclude the claimed methods of treatment could be identified given the lack of details necessary to identify those meeting the necessary functions. Though not controlling, the limitation of the working examples to a single method, is, nevertheless, a factor to be considered in a case involving physiological activity. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
Given the vast breadth of the genus of methods of treatment claimed, the unpredictability with respect to any amount of MSCs, any amount of alginic acid, applied in any way, not including a gelation step, and as a method of prevention it must be considered that these variables must be empirically determined and that Applicants have only enabled what they have specifically shown as supported by the art at the time of filing. Further, in an unpredictable art, the disclosure of only a limited number of examples utilizing specific subjects treated with the same exact composition applied in the same way in every case requiring gelation would represent to the skilled artisan that Applicants were not in possession of the claimed genus.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
To the extent the claims read on the enabled claim scope identified above, the following rejections are applied.
Claims 1-3, 6-8, 10, 12-14, 16-18, and 28-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ukeba, et al., EBioMedicine 53 (2020), hereinafter “Ukeba”, of record in the IDS filed 08 August, 2025.
Ukeba is a publication by several of the instant inventors. Ukeba discloses a method of treating degenerated intervertebral discs by injecting a 2% UPAL solution containing 1 x 106 BMSCs/ml into a cavity in the nucleus pulposus of a damaged intervertebral disc followed by injecting a 102mM CaCl2 solution on top of the UPAL/BMSC solution to induce gelation (Ukeba, Abstract; page 3, first full paragraph, and “2.8.” heading). UPAL is composed of sodium alginate which is a monovalent metal salt of alginic acid (Ukeba, page 2, “2.4.” heading). Thus, Ukeba discloses every limitation of instant claim 1. Regarding claims 2 and 17, the limitations are inherent properties of the composition used in the claimed method. It is noted that 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. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). Thus, for the purpose of applying prior art, a disclosure of an identical or substantially identical product is presumed to inherently possess the claimed properties. See MPEP 2112.01. Thus, the composition of Ukeba is presumed to inherently possess the claimed properties in claims 2 and 17. For completeness it is also worth noting that Ukeba discloses the MSCs activate and differentiate into nucleus pulposus cells (Ukeba, “Conclusions”). Regarding claim 3, the MSCs of Ukeba are BMSCs. It is noted that the BMSCs of Ukeba fall within the broadest reasonable interpretation of “highly-pure” considering the lack of a definition for this term and the fact that the BMSCs of Ukeba are commercially sourced BMSCs verified for their possession of an undifferentiated state (Ukeba, “2.3.” heading). Regarding claim 6, the composition is injected as a liquid (has fluidity) then gelation is induced after injection into a damaged intervertebral disc of a rabbit (subject in need thereof) (Ukeba, “2.6.”, “2.7.”, and “2.8.” headings). Regarding claim 7, the composition of Ukeba is applied to the nucleus pulposus. Regarding claim 8, the composition of Ukeba is filled into a defective site of the nucleus pulposus (Ukeba, “2.8.” heading). Regarding claim 10, the UPAL has decreased endotoxicity (Ukeba, page 2, first partial paragraph). Regarding claim 12, the concentration of alginic acid in Ukeba is 2% (w/v) (Ukeba, page 3, first full paragraph). Regarding claim 13, Ukeba discloses the composition is effective in preventing intervertebral disc degeneration (Ukeba, “Research in Context” heading). Regarding claim 14, Ukeba discloses treating intervertebral disc damage (Ukeba, “2.8.” heading). Regarding claim 16, Ukeba uses CaCl2 as a crosslinking agent to induce gelation (Ukeba, “2.8.” heading). Regarding claim 18, the BMSCs of Ukeba are in an undifferentiated state (Ukeba, “2.3.” heading). Regarding claims 28-29, The limitations that "intervertebral disc damage [is] associated with chronic low back pain" and “used to suppress intervertebral disc pain” are intended uses. The prior art composition taught by primary reference is capable of performing the recited intended use and, therefore, these limitations are met. See e.g. In re Schreiber, 128 F.3d 1473, 1477; 44 USPQ2d 1429, 1431 (Fed. Cir. 1997); MPEP 2114. Regarding claim 30, the crosslinking agent of Ukeba is Ca2+ which is a divalent metal ion.
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.
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.
To the extent the claims read on the enabled claim scope identified above, the following rejections are applied.
Claims 1, 3, and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Ukeba, et al., EBioMedicine 53 (2020), hereinafter “Ukeba”, of record in the IDS filed 08 August, 2025 in view of Mabuchi, et al., Stem cell reports 1.2 (2013): 152-165, hereinafter “Mabuchi”.
Ukeba discloses a method of treating degenerated intervertebral discs by injecting a 2% UPAL solution containing 1 x 106 BMSCs/ml into a cavity in the nucleus pulposus of a damaged intervertebral disc followed by injecting a 102mM CaCl2 solution on top of the UPAL/BMSC solution to induce gelation (Ukeba, Abstract; page 3, first full paragraph, and “2.8.” heading).
Ukeba does not disclose the use of CD271 positive or CD271 and CD90 double positive BMSCs as required by instant claims 4-5.
Mabuchi teaches the FACS isolation of an extremely pure population of MSCs from bone marrow which are LNGFR and Thy-1 positive (CD271 and CD90 positive respectively) (Mabuchi, Abstract; “Discussion” first paragraph; Figure 7). Mabuchi specifically teaches that the CD271+CD90+ BMSCs have increased clonogenic potential and that isolation of MSCs based on these two markers is a simple and easy method for obtaining extremely pure BMSCs (Mabuchi, “Discussion”, first paragraph). Regarding the characteristics recited in (a) and (b) of claims 4 and 5, it is noted that 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. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). Thus, for the purpose of applying prior art, a disclosure of an identical or substantially identical product is presumed to inherently possess the claimed properties. See MPEP 2112.01.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have selected CD271+CD90+ BMSCs via FACS as taught by Mabuchi and to have used those BMSCs in the method of repairing an intervertebral disc of Ukeba to arrive at the invention claimed in instant claims 4 and 5 with a reasonable expectation of success because they would have been motivated to do so to take advantage of a simple and easy method of isolating an extremely pure population of MSCs with high clonogenic potential.
Claims 1 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over US2020/0289547 (published: 17 September, 2020) (hereinafter “Sudo”) in view of Ukeba, et al., EBioMedicine 53 (2020), hereinafter “Ukeba”, of record in the IDS filed 08 August, 2025.
Sudo is another publication by the instant inventors. Sudo teaches a method of treating an intervertebral disc degeneration by injecting a composition comprising a monovalent metal salt of alginic acid into a nucleus pulposus of an intervertebral disc (Sudo, [0052]-[0053], [0239]). Sudo specifically teaches to use a monovalent metal salt of alginic acid which has an absolute molecular weight of 80,000 measured by GPC-MALS method (Sudo, [0037]). Sudo also teaches to use 0.5% to 5% w/w alginic acid concentration in the composition (Sudo, [0039]) and in particular a 2% w/v solution (Sudo, [0238]). Sudo also teaches to crosslink the composition with calcium ions (Sudo, [0042]-[0043]) and in particular a 102mM solution of calcium chloride (Sudo, [0239]). Lastly, Sudo suggests to include cells in the composition wherein the cells can be bone marrow mesenchymal stem cells in an amount between 1 x 104 and 1 x 107 cells per ml of the composition (Sudo, [0126]-[0128]).
While Sudo does not explicitly teach the composition to contain BMSCs, Sudo directly suggests to do so and directly suggests to use a concentration of cells which overlaps with the previously identified enabled claim scope. For determining how many cells and what particular type of cells to use in the composition of Sudo, a person having ordinary skill in the art would not have to look far because Ukeba provides these specific details and is also authored by the instant inventors. Ukeba discloses a method of treating degenerated intervertebral discs by injecting a 2% UPAL solution containing 1 x 106 BMSCs/ml into a cavity in the nucleus pulposus of a damaged intervertebral disc followed by injecting a 102mM CaCl2 solution on top of the UPAL/BMSC solution to induce gelation (Ukeba, Abstract; page 3, first full paragraph, and “2.8.” heading).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have used 1 x 106 BMSCs/ml as taught by Ukeba in the method of Sudo to arrive at the invention claimed in claims 1 and 11 with a reasonable expectation of success because Sudo directly suggests to include mesenchymal stem cells in an amount which overlaps with the enabled claim scope and Ukeba is published by the same instant inventors and teaches to use BMSCs at that concentration specifically.
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).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8, 10-14, 16-18, and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 12,478,636. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are an obvious variant of the patented claims.
Patented claim 1 reads: “A method of treating or reducing a degeneration and/or an injury of an intervertebral disc, wherein the degeneration and/or the injury comprises a defective site in a nucleus pulposus of the intervertebral disc, the method comprises applying to the defective site of a nucleus pulposus of an intervertebral disc in a subject in need thereof via a composition-filling inlet on the surface of the intervertebral disc a composition in a sol state to fill the defective site, the composition comprising a low endotoxin monovalent metal salt of alginic acid, and allowing a solid gel to form from a first portion of the composition after the applying by bringing a crosslinking agent into contact with the composition-filling inlet on the surface of the intervertebral disc, such that a second portion, which is other than the first portion, of the composition remains in the sol state, wherein the first portion corresponds to the surface of the composition located at the surface inlet and the second portion corresponds to the remainder of the composition other than the surface.”
Instant claim 1 reads: “A method of treating an intervertebral disc, comprising applying a composition comprising a monovalent metal salt of alginic acid and mesenchymal stem cells to the intervertebral disc of a subject in need thereof.”
Patented claim 1 is related to instant claim 1 as a species of the genus instantly claimed with the exception of the instant claims requiring mesenchymal stem cells in the composition. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann , 572 F.2d 312, 197 USPQ 5 (CCPA 1978). With regard to the requirement for mesenchymal stem cells in the composition, note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for ODP rejections.
In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
In the instant case, the patent specification teaches that the composition can comprise mesenchymal stem cells (col. 14, lines 46-50). Thus, the instantly claimed composition is an obvious variant of the composition claimed in the patent with regard to the inclusion of mesenchymal stem cells in the composition in the method of treating.
Conclusion
No claim is allowed.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA MARVICH/Primary Examiner, Art Unit 1634
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