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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 25, 2025 has been entered. All arguments have been fully considered. Claims 1, 6, 12-15, 30-33, 37-41, 53-54, 57-58, and 66-67 are currently pending. Claims 6, 12-15, 30-33, 37-41 and 53 are withdrawn. Claims 2-5, 7-11, 16-29, 34-36, 42-52, 55-56 and 59-65 are cancelled. Claims 1 and 66 are currently amended.
Claim Interpretation-Response to Remarks:
The Examiner appreciates Applicant’s remarks regarding the inadvertent reference to MPEP 2106 (II) (C) and 2111.02 (II) in reference to the recited functional language.
Further as to Applicant’s remarks regarding MPEP 2173.05, and the limitations directed to the composition being metabolized in 6 days or less it is noted that the recited limitations have been evaluated and considered in the context in which they are used. As previously discussed, the instant claims are not directed to a method of transplanting, implanting or injecting the composition to impart metabolization, if so, the limitation would be given patentable weight. The instant claims are directed to a composition, per se, and compositions are defined by their physical, structural, and chemical properties. The recited limitations regarding metabolization do not add further structure to the claimed composition. “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).” See MPEP 2112.01 (I).
Further as to Applicant’s remarks regarding the amended limitation “consisting of human cadaverous vertebral bone non-whole cellular components” it is noted Applicant’s remarks have been fully considered and the claim interpretation regarding this limitation is addressed below. Specifically, the amended limitation is likewise considered directed to the manner in which the bone marrow non-whole cellular components have been produced, i.e., derived from the vertebral bone of a human cadaver. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the non-whole cellular components of bone marrow material has been produced is not sufficiently detailed so as to impart any unique structural/chemical properties to the composition, rather non-whole cellular components even if obtained from a live donor, or obtained from human bones other than vertebral bones (e.g., femoral bones), would appear to read on the claimed mixture of non-whole cellular bone marrow material, even if obtained from a live donor, or obtained from human bones other than vertebral bones.
Claim Interpretation
It is noted the following limitations are directed to the intended use of the cryopreserved coated biological composition and do not add further structure to the claimed composition:
“An aqueous, injectable…” (claim 66) and “The aqueous injectable…” (claim 67) are interpreted as intended use since the claims do not further recite physical limitations regarding viscosity that would correlate to permitting injection.
Further regarding claims 1 and 66 and the limitations reciting “is metabolized in 6 days or less after injection of a flowable mixture comprising a volume of fluid and the cryopreserved……into a disc or cartilage of a patient” (claim 1) and “…is metabolized in 6 days or less after injection of the aqueous, injectable, coated biological composition into a disc or cartilage of a patient” (claim 66), it is noted that, given the claims are directed to a composition and are not directed to a method of implanting the composition, these recitations are interpreted as functional language meaning the polyampholyte coated biological composition is capable of being metabolized over a time of 6 days or less after implantation, and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product.
However, it is additionally noted, “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).” See MPEP 2112.01 (I).
Claims 1 and 66 have been amended to recite limitations that are considered product-by-process limitations.
Claim 1 recites “…a mixture of bone marrow material consisting of human cadaverous vertebral bone non-whole cellular components…” and claim 66 recites “…bone marrow material consisting of human cadaverous vertebral bone non-whole cellular components…”
It is noted that such limitations are directed to the manner in which the bone marrow non-whole cellular components have been produced, i.e., derived from the vertebral bone of a human cadaver. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the non-whole cellular components of bone marrow material has been produced is not sufficiently detailed so as to impart any unique structural/chemical properties to the composition, rather non-whole cellular components even if obtained from a live donor, or obtained from human bones other than vertebral bones (e.g., femoral bones), would appear to read on the claimed mixture of non-whole cellular bone marrow material, even if obtained from a live donor, or obtained from human bones other than vertebral bones.
New Ground of Rejection, necessitated by Amendment
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 1, 54, 57-58, 66 and 67 remain 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 “unaltered native proteoglycans” in claims 1 and 66 is a relative term which renders the claim indefinite. The term “unaltered native proteoglycans” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The specification at [0049] discloses the following:
[0049]"Nucleus Pulposus" - Nucleus pulposus is the gel-like substance in the middle of the spinal disc. It is the remnant of the notochord. It functions to distribute hydraulic pressure in all directions within each disc under compressive loads. The nucleus pulposus consists of large vacuolated notochord cells, small chondrocyte-like cells, collagen fibrils, and proteoglycan aggrecans that aggregate through hyaluronic chains. Attached to each aggrecan molecule are the glycosaminoglycan (GAG) chains of chondroitin sulfate and keratan sulfate. Aggrecan is negatively charged, allowing the nucleus pulposus to attract water molecules. The amount of water and glycosaminoglycans decreases with age and degeneration.
The specification at [0053] discloses the following:
[0053]"Proteoglycans" - Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a Serine (Ser) residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge (e.g. chondroitin sulfate-GlcA-Gal-Gal-Xy-PROTEIN). The Serine residue is generally in the sequence -Ser- Gly-X-Gly- (where X can be any amino acid residue, but Proline), although not every protein with this sequence has an attached glycosaminoglycan. The chains are long, linear carbohydrate polymers that are negatively charged under physiological conditions, due to the occurrence of sulfate and uronic acid groups. Proteoglycans occur in the connective tissue. Proteoglycans are a major component of the animal extracellular matrix, the "filler" substance existing between cells in an organism. Here they form large complexes, both to other proteoglycans, to hyaluronan and to fibrous matrix proteins (such as collagen). They are also involved in binding cations (such as sodium, potassium and calcium) and water, and also regulating the movement of molecules through the matrix. Evidence also shows they can affect the activity and stability of proteins and signaling molecules within the matrix. Individual functions of proteoglycans can be attributed to either the protein core or the attached GAG chain and serve as lubricants.
However, the specification does not provide any other information regarding the metes and bounds of “unaltered native proteoglycans”. It is unclear in what manner the native proteoglycans are “unaltered”. Does the claim mean they do not have a reduced water content, or the number/amount of glycosaminoglycans that are attached are not reduced or increased, or does the limitation mean the core protein is not altered, or the number of proteoglycan complexes are unaltered in number or size? It is unclear how the native proteoglycans remain unaltered upon subjecting to freeze-drying and cryomilling as disclosed at Applicant’s specification at paragraph [00148].
Given the specification does not define what is meant by “unaltered native proteoglycans”, one of ordinary skill in the art would not understand the metes and bounds of the term.
Claims 54, 57-58 and 67 are included in this rejection based on their dependency to claims 1 or 66.
Rejection Maintained, Updated in view of Amendment
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.
RE: Rejection of Claims 1, 54, 57-58, 66 and 67 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:
Applicant’s amendment submitted 11/25/2025 has removed the limitation:
“wherein the nucleus pulposus particles are not treated to remove proteoglycans”, thus obviating the previous rejection of record.
However, it is noted Applicant’s amendment submitted 11/25/2025 has added the limitation “…wherein the nucleus pulposus particles comprise unaltered native proteoglycans…”
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. The amended limitation “…wherein the nucleus pulposus particles comprise unaltered native proteoglycans…” is not supported by the original disclosure; therefore, the limitation is considered new matter.
In the instant case is noted Applicant points to the specification at paragraphs [0049], [0145], [0149] and [0158] as support for the amended limitation. However, paragraphs [0049], [0145] and [0149] do not disclose any specific treatments that the nucleus pulposus particles are subjected to, or what types of treatments result in “unaltered” native proteoglycans. Paragraph [0158] is directed to cartilage compositions.
The specification, as a whole, does not disclose any specific treatments that are applied, or not applied, to the nucleus pulposus, or that there are specific treatments that produce “unaltered” proteoglycans. The specification at paragraph [00149] teaches the obtained nucleus pulposus is freeze-dried, and thus at a minimum the water content is altered, and paragraph [00149] further discloses cryomilling the freeze-dried nucleus pulposus to produce a micronized material, thus the native proteoglycans have been fractured by milling thus altering their native size.
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.
Rejection(s) Maintained
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 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.
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 54 and 57-58 remain rejected under 35 U.S.C. 103 as being unpatentable over Ferree et al., (US 2008/0014179; previously cited) (“Ferree”), in view of Liu et al., (Nanoscale, 2017, Vol. 9, pages 4430-4438; previously cited) (“Liu”), Mitsialis et al., (US 2014/0065240; see previously cited) (“Mitsialis”), Badiavas et al., (WO 2014/159662, previously cited) (“Badiavas”), Nishimura et al., (Spine, 1998, Volume 23, Issue 14, pages 1531-1538; previously provided), Matsumura et al., (US 2011/0172315; previously cited) (“Matsumura 2011”), as evidenced by Weston et al., (BioDrugs (2019) 33: 137-158; previously cited) (“Weston”), Shi et al., (Food & Nutrition Research 2016, 60: 31891, 8 pages; previously cited) (“Shi”) and Hiraki et al., (Regulatory Toxicology and Pharmacology 37 (2003) 328-340; previously cited) (“Hiraki”).
It is initially noted the rejection has been updated in view of Applicant’s amendment now requiring the limitation “wherein the nucleus pulposus particles comprise unaltered native proteoglycans.”
It is further noted that claim 1 is interpreted as being directed to a cryopreserved composition comprising:
(1) a mixture of human non-whole cellular bone marrow material as claimed,
(2) a volume of nucleus pulposus particles having a size of 400 microns or less, wherein the nucleus pulposus particles comprise unaltered native proteoglycans,
(3) a volume of liquid protectant intermixed with the mixture of bone marrow material and the nucleus pulposus particles, and thus the combined components include the recited protectant and thus coated by the protectant.
The claimed cryopreserved coated composition encompassed by claim 1 comprises a combination/admixture of (1) a mixture of human bone marrow material consisting of non-whole cellular components including vesicular components, active and inactive components of biological activity, cell fragments, organelle fragments, cellular excretions, cellular derivatives, and extracellular components, (2) a volume of nucleus pulposus particles having a size of 400 microns or less, wherein the nucleus pulposus particles comprise unaltered native proteoglycans, (3) a volume of a liquid protectant that is a polyampholyte protectant of a polyamine polymer compound having a pH of 7.4 and exhibits a positive field charge wherein the polyampholyte protectant is a cryoprotectant and is intermixed and enveloping the non-whole cellular components and the nucleus pulposus particles.
Regarding claim 1, Ferree is directed to methods and compositions for treating defective tissue such as intervertebral discs or articular cartilage. Ferree teaches the composition contains isolated donor tissue (e.g., nucleus pulposus tissue) that has been enzyme-treated to reduce the amount of proteoglycans in the donor tissue compared to untreated tissue. Ferree teaches the addition of cells is optional, thus Ferree’s teaching encompasses an embodiment that does not include whole cells (Abstract and paragraphs [0014], [0016], [0020], [0031] and [0087]-[0089]).
Ferree, at paragraphs [0018] and [0052], teaches the isolated nucleus pulposus tissue is morselized (i.e., nucleus pulposus particles) and enzyme-treated to form particles having an average size ranging from about 0.01 mm3 to 30 mm3 (correlates to 10 µm3 to 30,000 µm3, claimed range lies within the prior art range). Ferree, at paragraph [0051], teaches the isolated donor tissue is morselized to enable insertion of the enzyme-treated tissue into a patient's body through an injection. Ferree’s paragraph [0117] also teaches delivery by injection. Additionally, Ferree also teaches freezing the nucleus pulposus (NP) for storage prior to thawing and resuspension for future use (Example 4, paragraph [0128] and Example 6, paragraph [0131]).
Ferree’s claims 1 and 7 claim the following:
A biomedical material, comprising: an enzyme-treated isolated donor tissue, the enzyme-treated donor tissue characterized by a reduced amount of at least one type of proteoglycan compared to untreated tissue.
7. The biomedical material of claim 1, wherein the enzyme-treated isolated donor tissue is an intervertebral disc tissue selected from the group consisting of: nucleus pulposus tissue; annulus fibrosis tissue; and a combination thereof.
Ferree’s claim 13-15 claim the following treatment method:
13. A method of treating a defective tissue in a subject, comprising: introducing a biomedical material of claim 1 into a subject having a defective tissue. 14. The method of claim 13, wherein the defective tissue is an intervertebral disc. 15. The method of claim 13, wherein the defective tissue is articular cartilage.
Thus, Ferree’s teaching encompasses a tissue regenerative composition for treating defective intervertebral discs and cartilage, wherein the composition comprises cell-free nucleus pulposus tissue particles having an average size ranging from about 0.01 mm3 to 30 mm3.
As to the newly amended limitation regarding a volume of “nucleus pulposus particles comprise unaltered native proteoglycans”, it is noted that Applicant’s specification does not provide a specific definition for the term “unaltered native proteoglycans”. However, Applicant’s specification does indicate that gradual desiccation and loss of proteoglycan content is a ‘normal’ part of disc aging [0043], thus “unaltered native proteoglycans” would encompass nucleus pulposus particles having reduced proteoglycan content or that the proteoglycans having a loss of moisture content. Applicant’s specification further indicates that the claimed nucleus pulposus particles are prepared by freeze-drying and cryomilling ([00149]).
It is noted that, although Ferree teaches subjecting the nucleus pulposus particles to an enzyme treatment that reduces the amount of the proteoglycan content ([0016]), it is considered that Ferree’s remaining proteoglycans read on “unaltered native proteoglycans”.
Ferree differs from the instant invention in that Ferree does not further teach the cartilage regenerative composition includes a mixture of human bone marrow material that consists of non-whole cellular components as indicated in claim 1. However, Liu is directed to the use of human stem cell-derived exosomes (extracellular nanovesicles, i.e., non-whole cellular vesicular components) for cartilage regeneration, which provides a cell-free therapy for wound repair (Abstract and Conclusion). Liu teaches that stem cell-derived exosomes provide tissue regeneration therapy that is analogous to stem cell-based therapies, without the safety concerns of direct cell transplantation, thus providing acellular factors for cartilage regeneration that replace cell-based therapies (Introduction, right column, second paragraph, page 4430 to left column, first paragraph, page 4431).
Thus, given that the intention of Ferree is to prepare tissue engineering compositions for cartilage repair (paragraph [0217]), it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to modify the composition of Ferree to include stem-cell derived exosomes, as taught by Liu, for the predictable result of successfully producing a tissue engineering composition for cartilage repair, thus meeting the limitations of claim 1.
One of ordinary skill in the art would have been motivated to modify the composition of Ferree in order to produce a tissue engineering composition that promotes cartilage repair and regeneration. Liu has shown the human stem cell-derived exosomes promote cartilage repair that is analogous to stem cell-based therapies, without the safety concerns of direct cell transplantation; thus, one would have had a reasonable expectation of successfully including exosomes in the cartilage engineering composition of Ferree.
Combination of multiple products each known to have the same effect to produce a final product having the same effect is prima facie obvious. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
It is noted that Weston evidences that exosomes necessarily contain bioactive lipids, cytokines, growth factors (cellular excretion), receptors (cellular derivative), transcription factors, DNA, non-coding regulatory RNAs (inactive components of biological activity) and messenger RNAs (mRNAs) (active components of biological activity, fragments of ribosomes (i.e. organelles)) (1. Introduction, page 137), and are formed by inward budding of the plasma membrane (vesicular components, cell fragments) and thus include extracellular components such as cell surface proteins and fragments of the cell membrane (as illustrated in Weston Fig. 1, page 138).
Therefore, the exosomes of Liu necessarily include a mixture of vesicular components and active and inactive components of biological activity, cell fragments and organelle fragments, cellular excretions, cellular derivatives and extracellular components, absent evidence to the contrary, thus meeting the limitation of claim 1.
Liu differs from the instant invention in that Liu does not disclose whether or not the therapeutic exosomes are derived from bone marrow material. However, Mitsialis teaches therapeutic compositions comprising exosomes obtained from bone marrow mesenchymal stem cell (BM-MSC) conditioned medium and the presence of the exosomes was verified by negative staining microscopy (Abstract and paragraph [0030]). Badiavas also teaches tissue regenerative microvesicle compositions comprising exosomes that are derived from bone marrow material. Badiavas teaches the compositions containing the exosomes enhances wound healing and reduces the formation of scar tissue (Abstract; page 1, first paragraph; Examples 3, 5, 8 and 14; claims 6 and 7).
Therefore, in considering the teachings of Mitsialis and Badiavas, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute bone marrow-derived exosome compositions, as the source of the therapeutic exosomes in the composition of Ferree, in view of Liu.
The person of ordinary skill in the art would have been motivated to use human bone marrow-derived exosome compositions, as taught by Mitsialis and Badiavas, for the predictable result of providing therapeutic exosomes from a well-known source.
The skilled artisan would have had a reasonable expectation of success in substituting the exosomes derived from bone marrow material because Mitsialis and Badiavas have shown well-known methods for obtaining bone marrow-derived exosome compositions and bone marrow-derived exosome compositions have therapeutic effects, including enhancing wound healing and reducing the formation of scar tissue.
As to the limitation that the biologic mixture is compatible with biologic function, Liu, Mitsialis and Badiavas each teach the exosome compositions have therapeutic, tissue regenerative properties, thus meeting the limitation of claim 1.
As to the limitation regarding a volume of a liquid protectant intermixed with the mixture of bone marrow material and the nucleus pulposus particles, it is noted, as set forth above, Ferree teaches frozen storage of the composition prior to thawing and resuspension for treatment (Examples 4 and 6) and Mitsialis, at paragraph [0063], specifically teaches that the invention contemplates the long-term storage of the exosomes in the cryopreserved state in freezing medium prior to thawing and administration. The freezing medium contains additives to enhance preservation of the composition’s biological activity and these additives will be similar to those used for cryopreservation of intact cells, such as DMSO, glycerol and polyethylene glycol (i.e., protectant). Thus, Mitsialis teaches the inclusion of cryoprotectants for frozen storage.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include cryoprotectants for frozen storage.
The person of ordinary skill in the art would have been motivated to modify the composition comprising exosomes and nucleus pulposus particles to include a cryoprotectant agent that enhances preservation of the biological activity, as taught by Mitsialis, for the predictable result of successfully permitting long-term storage and preservation of the composition for future therapeutic use, thus meeting the limitation of claim 1.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of the cited prior art because each of these teachings are directed at tissue regenerative compositions.
Further regarding claim 1, although Mitsialis renders obvious using a cryoprotective agent, such as DMSO, for the frozen preservation of the biologic composition, Mitsialis does not further teach the protectant is a polyampholyte cryoprotectant of carboxylated polylysine and wherein the polyampholyte protectant is free of any DMSO or glycerol, as recited in claim 1. However, Matsumura 2011 is directed to cryopreserving biological compositions, e.g., cells, in a safe manner without using toxic substances such as DMSO (Abstract and paragraphs [0017]). Matsumura 2011 specifically teaches using polyamines, including carboxylated poly-L-lysine, e.g., ε-poly-L-lysine, since it is less toxic that DMSO and does not require washing after thawing the biological compositions (paragraphs [0022], [0036], [0039] and [0057]). Matsumura 2011 teaches the polymer cryopreservative is applicable to frozen or freeze-dried pharmaceuticals (paragraph [0039]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute a polyampholyte cryoprotectant such as carboxylated poly-L-lysine (COOH-PLL), as the cryoprotectant agent in the prior art composition that contains exosomes and nucleus pulposus thus forming the coated biological composition.
The person of ordinary skill in the art would have been motivated to use a polyampholyte cryoprotective agent such as carboxylated poly-L-lysine, as taught by Matsumura 2011, for the predictable result of providing a more effective cryoprotectant with reduced toxicity, thus making it safer to immediately use the preserved material upon thawing, and improving efficiency since the cryoprotectant does not need to be removed from the thawed composition prior to transplantation.
The skilled artisan would have had a reasonable expectation of success in substituting the polyampholyte cryoprotectant, e.g., COOH-PLL, for the DMSO protectant because Matsumura 2011 has shown that polyampholyte protectants such as carboxylated poly-L-lysine (COOH-PLL) show higher preservation efficiency than the conventional CPAs, have reduced toxicity and improve efficiency since the composition can be immediately employed without needing to remove the cryoprotectant before administration.
As to the limitation that the liquid protectant has a pH of 7.4, it is noted that Matsumura 2011 further teaches adjusting the pH of the cryopreservation solution comprising poly-L-lysine to a pH ranging from 7.0 to 8.0 prior to cryopreservation (paragraph [0042]), thus the claimed range lies within the prior art range. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Further regarding claim 1 and the limitation that the liquid protectant exhibits a positive field charge that forms a hydrophilic coating, it is noted that Hiraki evidences that ε-Polylysine molecules are cationic (positively charged) molecules due to their positively charged amino groups in water and have hydrophilic carboxyl groups on the outside of the molecule polar solutions (e.g., aqueous solutions) (1. Introduction, left col., third paragraph, page 329). Thus, Matsumura’s disclosed ε-Poly-L-lysine (PLL) is considered to exhibit a positive field charge that forms a hydrophilic coating, absent evidence to the contrary.
As to the limitation that the composition is a cryopreserved composition, it is noted that Ferree teaches frozen storage of nucleus pulposus and Nishimura further teaches cryopreservation of nucleus pulposus, e.g., mixed with a liquid protectant (Abstract, Results, page 3 of 13; Materials and Methods, Surgical Procedure, third paragraph, page 4 of 13).
Mitsialis, at paragraph [0063], specifically teaches long-term storage of the bone marrow-derived exosomes in a cryopreserved state.
Matsumura 2011 teaches cryopreservation of therapeutic pharmaceutical compositions (paragraph [0039]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to cryopreserve the therapeutic composition.
The person of ordinary skill in the art would have been motivated to modify the therapeutic composition of the combined prior art to include cryopreservation of the composition, as taught by Ferree, Nishimura, Mitsialis and Matsumura 2011, for the predictable result of successfully permitting long-term storage and preservation of the composition for future therapeutic use, thus meeting the limitation of claim 1.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of the cited prior art because each of these teachings are directed at tissue regenerative compositions.
Further regarding claim 1 and the limitation “…wherein the liquid protectant…. forms a hydrophilic coating externally enveloping each of the non-whole cellular components of the mixture of bone marrow material and each of the nucleus pulposus particles…”, it is noted that Matsumura 2011 discloses the same polyampholyte cryoprotectant as disclosed in the instant specification (paragraph [0019]). Thus, absent evidence to the contrary, because Matsumura 2011 discloses the same polyampholyte protectant as disclosed in the instant application, the polyampholyte cryoprotectant would necessarily envelope each of the non-whole cellular components and the nucleus pulposus particles of the mixture of biologic material and externally protect the non-whole cellular components and the nucleus pulposus particles, as recited in claim 1.
As to the limitation “…the cryopreserved coated biological composition is metabolized in 6 days or less after injection…”, it is noted, as set forth above at Claim Interpretation, the instant claims are directed to a composition and do not positively recite any active steps regarding injection. Thus, the recited limitation is directed to a functional limitation that occurs after implantation and is therefore interpreted as meaning the polyampholyte coated biological composition is capable of being metabolized over a time of 6 days or less after implantation.
Although Matsumura 2011 does not further comment on the biodegradation or metabolism of the polyampholyte carboxylated poly-L-lysine coating, i.e., metabolized in 6 days or less after injection, it is noted Shi teaches that, in addition to being edible and nontoxic to humans, poly-L-lysine is biodegradable (i.e., metabolized) (page 2, col. 1, first full paragraph) and Hiraki conducted various assays to determine the metabolic profile of ε-poly-L-lysine which revealed 92.9% of the poly-L-lysine was eliminated in feces by 48 hours (2 days), the excretion half-life in plasma was 3.9 days and HPLC profiles at 8-72 hours show diminishing levels of ε-poly-L-lysine and L-lysine in plasma (Abstract). Thus, it is considered that Shi and Hiraki evidence the polyampholyte ε-poly-L-lysine coating disclosed by Matsumura 2011 is capable of being metabolized over a time of 6 days or less after implantation.
Additionally, it is noted that Matsumura 2011 teaches the same polyampholyte ε-poly-L-lysine as disclosed in the instant application. Thus, a chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art composition does not inherently possess the same properties as instantly claimed composition.
Regarding claim 54 and the limitation that the protectant is a 1-50 w/w % aqueous solution, Matsumura 2011 teaches the liquid protectant is used at concentrations including 7.5% and 25% (paragraphs [0042] and [0044]) (claimed range overlaps the prior art range), thus meeting the limitation of claim 54. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Matsumura 2011 further teaches that the cryoprotective agent (CPA) is carboxylated poly-l-lysine (COOH-PLL), specifically Ɛ poly-l-lysine ([0042], [0045] and [0048]), as recited in claim 54.
Further regarding claim 54, as to the limitation “50-99 mol % of amino groups, other than those forming amino-acid-to-amino-acid linkages, of said at least one polymer compound is blocked with carboxylic anhydride to form pendant moieties, each of which is linked to main chain of the polymer via an amide linkage and essentially has a not-blocked carboxylic group”, Matsumura 2011 teaches 10%, 25%, 43%, 50%, 60% and 76% of amino-groups are blocked with succinic anhydride (carboxylic anhydride) (claimed range overlaps the prior art range), thus meeting the limitation of claim 54. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
The conversion method used by Matsumura 2011 is substantially identical to the method taught in the instant application at paragraph [00137]; thus, absent evidence to the contrary, because conversion method used by Matsumura 2011 is the same as in the instant application, the method would necessarily have the amino groups, other than those forming amino-acid-to-amino-acid linkages, of said at least one polymer compound is blocked with carboxylic anhydride to form pendant moieties, each of which is linked to main chain of the polymer via an amide linkage and essentially has a not-blocked carboxylic group.
Under the principles of inherency, when the prior art method is the same as a method described in the specification for carrying out the claimed method, it can be assumed the method will inherently perform the claimed process. See In re Best, 562 F. 2d, 1252, 1255, 195 USPQ 430, 433 (CCPA 1977) and Ex parte Novitski, 26 USPQ 2d 1389 (Bd. Pat. App. & inter. 1993). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of filing, but only that the subject matter is in fact inherent in the prior art reference. See Schering Corp. v. Geneva Pharm. Inc, 339 F.3d 1373, 1377, 67, USPQ2d 1664, 1668 (Fed. Cir. 2003). See also Toro Co. v. Deere & Co. 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004). MPEP 2112.01
Regarding claim 57, Matsumura 2011 discloses the Ɛ- poly-L-lysine have the average molecular weights of 1000-20,000, and particularly those of 1000-10,000 ([0035]), thus the claimed range overlaps the prior art range, thus meeting the limitation of claim 57. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Regarding claim 58, as set forth above regarding claim 54, Matsumura 2011 teaches 10%, 25%, 43%, 50%, 60% and 76% of amino-groups are blocked with succinic anhydride (carboxylic anhydride). Matsumura 2011 teaches the blockage is done by the carboxylation or acetylation of the amino groups to the degrees of preferably 50-99 mol %, particularly 50-93 mol %, more preferably 50-90 mol %, still more preferably 55-80 mol %, and the most preferably 58-76 mol %. About 50% of the amino group would be blocked by being reacted with 52-53 mol % of anhydrous carboxylic acid on basis of molar amount of the amino groups in the polyamine. In a normal reaction condition, 90-95% of the amino groups would be blocked when reacted with 100 mol % anhydrous carboxylic acid ([0036]). The conversion method used by Matsumura 2011 is substantially identical to the method taught in the instant application at paragraph [00137]; thus, absent evidence to the contrary, because conversion method used by Matsumura 2011 is the same as in the instant application, the method would necessarily have remaining side-chain amino groups or remaining side-chain and terminal amino groups of the at least one polymer compound that are not blocked by covalent bonding.
Claim(s) 66-67 remain rejected under 35 U.S.C. 103 as being unpatentable over Ferree, in view of Liu, Mitsialis, Badiavas, Nishimura, and Matsumura 2011, as evidenced by Weston, Shi and Hiraki, as applied to claims 1, 54, 57 and 58 above, and further in view of Weston et al., (US 2016/0256490, published Sep. 8, 2016; previously cited) (“US ‘490”).
The teaching of Ferree, in view of Liu, Mitsialis, Badiavas, Nishimura, and Matsumura 2011, as evidenced by Weston, Shi and Hiraki is set forth above.
Regarding claims 66 and 67, it is noted, as set forth above regarding claim 1, the combined prior art renders obvious a cryopreserved coated biological composition comprising:
(a) bone marrow material consisting of non-whole cellular components, wherein the non-whole cellular components are obtained from human bone marrow;
(b) nucleus pulposus particles containing some percentage of proteoglycans; and
(c) a polyampholyte cryoprotectant of carboxylated polylysine free of DMSO or glycerol, wherein the polyampholyte cryoprotectant protectant has a pH of about 7.4 and forms a hydrophilic coating externally enveloping each of the non-whole cellular components of the bone marrow material and each of the nucleus pulposus particles.
As to the limitation “…wherein the coated biological composition is metabolized in 6 days or less after injection of the aqueous, injectable, coated biological composition into a disc or cartilage of a patient…”, it is noted, as set forth above at Claim Interpretation, the instant claims are directed to a composition and do not positively recite any active steps regarding injection. Thus, the recited limitation is directed to a functional limitation that occurs after injection and is therefore interpreted as meaning the composition is capable of being metabolized over a time of 6 days or less after injection.
Additionally, as discussed above, it is considered that Shi and Hiraki evidence the polyampholyte ε-poly-L-lysine coating disclosed by Matsumura 2011 is capable of being metabolized over a time of 6 days or less after implantation.
Moreover, it is noted that Matsumura 2011 teaches the same polyampholyte ε-poly-L-lysine as disclosed in the instant application. Thus, a chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art composition does not inherently possess the same properties as instantly claimed composition.
The only difference between the combined prior art and the instant invention is that the combined prior art does not further teach an aqueous composition, i.e., in a thawed, liquid state and no longer in a frozen state.
However, it is noted that US ‘490 is directed to compositions comprising bone marrow material that consists of non-whole cellular components which include vesicular components, active and inactive components of biological activity, cell fragments, cellular excretions, cellular derivatives, and extracellular components in combination with a polyampholyte cryoprotectant (Abstract; [0007], [0012] and [0018]; claim 1 and 15), wherein, when the composition has been cryopreserved, the composition is thawed and diluted in saline for subsequent use as an injectable composition for treating patients, i.e., an aqueous injectable composition ([0012]; claim 27). Thus, US ‘490 has established it is well-known to prepare cryopreserved compositions comprising non-whole cellular components and polyampholyte cryoprotectants as aqueous compositions for use as injectable therapeutic compositions.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare cryopreserved compositions as aqueous compositions for use as injectable therapeutic compositions.
The person of ordinary skill in the art would have been motivated to modify the prior art cryopreserved composition to be formulated as a thawed, aqueous composition, as taught by US ‘490, for the predictable result of successfully providing a therapeutic composition that is easy to administer via injection, thus meeting the limitation of claim 66.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of the combined prior art and US ‘490 because each of these teachings are directed at tissue regenerative compositions.
Regarding claim 67, it is noted that Matsumura 2011 specifically teaches using polyamines, including carboxylated poly-L-lysine, e.g., ε-poly-L-lysine, thus meeting the limitation of claim 67.
Response to Applicant’s Remarks
Rejections under 35 USC 103:
As to Applicant’s remarks regarding the reference to claim 1 in the Final Action, pages 9-10 (as discussed at Applicant’s remarks, page 7), it is noted, said reference to claim 1 identifies the components encompassed by claim 1, in view of the product-by-process language and intended use/functional language.
Applicant has traversed the rejection of record on the grounds that the primary reference teaches away from nucleus pulposus particles comprising unaltered native proteoglycans, as discussed at pages 8-10. Applicant’s remarks have been carefully considered, but are not found persuasive.
In response, it is first noted, as set forth above at the new ground of rejection under 35 USC 112 regarding the limitation directed to nucleus pulposus particles comprising unaltered native proteoglycans, said amended limitation is considered new matter and indefinite. The term “unaltered native proteoglycans” is not defined by the claim and the specification does not provide a standard for ascertaining the requisite degree, the specification does not specifically define the metes and bounds of ‘unaltered’ native proteoglycans. Paragraphs [0049], [0145] and [0149] do not disclose any specific treatments that the nucleus pulposus particles are subjected to, or what types of treatments result in “unaltered” native proteoglycans, thus one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. On the contrary, paragraphs [0148]-[0149] discloses the recovered nucleus pulposus is subjected to freezing and drying thus resulting in removing moisture to under 5%, thus the water content of the proteoglycans is altered. Paragraphs [0148]-[0149] further discloses cryomilling the freeze-dried nucleus pulposus, thus the physical structure of the proteoglycans is altered, as evidenced by Quijano et al., (see PTO-892). Quijano teaches the preparation of decellularized nucleus pulposus (DNP) particles whi