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 .
Election/Restrictions
Applicant’s election without traverse of Group I claims 36-42 and 48 in the reply filed on 03/10/2026 is acknowledged.
Claims 43-47,49-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/10/2026.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
The rejection of claims 36 and 38-42 under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter is withdrawn in light of the amendment to claim 36, incorporating the limitations of claim 37 that requires the fibrillin and collagen be fragmented
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 39-41 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The nature of the invention relates to obtaining an extracellular matrix (ECM) from adipose tissue that is free of cells, nucleic acids and lipids.
The claims are broad with regard to the protein content and source material of the hydrogel composition.
The specification teaches obtaining ECM from human adipose using a method that comprises freezing human adipose tissue, slicing the tissue, denaturing the slice of tissue with guanidine HCl, mechanically homogenizing the tissue to lyse the cellular material, contacting the tissue with nucleases, followed by acid/pepsin and dialysis. These steps affect the composition in terms of what proteins remain and the size of their fragments.
With regard to species, Mariman (Cellular and Molecular Life Sciences, Volume 67, pages 1277–1292, 2010) taught that the function of ECM depends on its molecular makeup and that overall, adipocyte ECM comprises the same proteins as other ECMs but the relative quantity affects the properties of the ECM from various sources. At page 1278, col. 2, Mariman states that findings suggest species- or fat depot-specific differences. Table 1 lists many different known ECM proteins and shows variability in the presence of the proteins between species of mammal and between subtypes of adipocyte within a species.
Song (MOLECULAR MEDICINE REPORTS 17: 138-146, 2018) taught a method of preparing human subcutaneous adipose ECM that comprised 6 freeze-thaw cycles to disrupt cells followed by exposure to a polar solvent to remove lipids, then subjected to trypsin and DNase and RNase to digest proteins and nucleic acids. The resulting ECM comprised a collagen fiber scaffold comprising mostly collagen IV and laminin (page 143). Brown (2011, Tissue Engineering Part C: Methods, 17, pages 411-421) taught “Numerous studies have shown that the methods by which ECM scaffold materials are prepared have a dramatic effect upon both the biochemical and structural properties of the resultant ECM scaffold material as well as the ability of the material to support a positive tissue remodeling outcome after implantation” (Abstract). A comparison of three different protocols demonstrated that the resulting scaffold structures were distinct from a biochemical and structural perspective.
The specification teaches a method that comprises use of guanidine HCl which mainly denatures globular proteins but at higher concentrations, can partially denature fibrous proteins (collagen and fibrillin, for example). This step will alter the ECM structure. Accordingly, rather than being comprised of large collagen fibers over 100 kDa, the specification teaches the presence of collagen fragments ranging from 10-30 kDa with an average of 20 kDa. Didangelos (Mol Cell Proteomics. 2010 Jun 15;9(9):2048–2062) taught 4M guanidine HCl is effective in solubilizing most ECM components leaving behind only the insoluble, heavily cross-linked type I and III collagens and elastin. This is consistent with the use of 4M guanidine HCl in the specification that results in smaller collagen fragments.
With regard to claims 39,40 and 41, the specification does not characterize the resulting hydrogel to support that it meets the claimed amount of fibrillin (claim 39) or claimed ratios of proteins (claims 40-41). Given the guidance in the art with regard to the variability of ECM scaffolds following different decellularization protocols, evidence supporting the claimed ratios is a result of the method used in the specification is necessary. It is noted that the specification teaches that the defined size fragments from collagens and fibrillin was achieved through specific chemical extraction and digestion protocols. Thus, the specification and art support that it would require undue experimentation to determine how to make a hydrogel composition as specifically set forth by claims 39-41.
Applicant’s Remarks have been fully considered but are not persuasive. Applicant points to paragraphs 133-135 that the composition of the hydrogel was characterized and is as claimed. This is not persuasive because the Specification at paragraphs 133-135 set forth the protocol (para 133-134) and para 135 discusses that defined fragment sizes of COL1A1, COL1A2, COL3A1, COL4A2, COL5A2, and FBN1 observed by mass spectrometry and COL1A1, COL1A2, COL3A1, COL4A2, COL5A2 fragments were, on average 20kDa. There is no discussion of the size of fibrillin. Para 135 continues by discussing the sizes of the fragments as “COL1A1>COL1A2>COL3A1>COL4A2>COL5A2”, meaning that the COL1A1 fragments were the larger one and COL5A2 were smaller in size. There is no discussion of fibrillin size and no discussion of the concentrations of the collagens or fibrillin as limited by claims 39 and 40.
Applicant also points to paragraph 98 for support. Para 98 is prophetic and refers to potential embodiments. There is nothing to link these particular embodiments to the hydrogel that results from the working example, which uses a highly specific protocol.
Written Description
Claim 48 remains 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.
Claim 48 is drawn to an isolated hydrogel composition prepared by the method of claim 43. The specification fails to describe the characteristics of a hydrogel obtained by the claimed method such that one of skill in the art could envision the properties of a hydrogel made by the process of nonelected claim 43. The specification teaches a highly specific protocol that uses guanidine HCl to extract fibrous proteins by denaturing non-fibrous/globular proteins, followed by pepsin treatment, which leads to fragments of fibrous proteins. The process of the product by process claim 48, now recites use of guanidine HCl as a denaturant and pepsin to digest the fibrous proteins. However, digestion times and temperatures are not limited and varying such lead to variations in peptide content and size in the same manner as varying proteases. The size of the collagen fragments affects the gelling properties of the hydrogel. This is not an issue of enablement, rather one of description. The skilled artisan cannot envision the composition of the various hydrogels that can result from variations allowed by the generic nature of claim 43. For example, Kim (Tissue Eng Regen Med (2024) 21(1):97–109; IDS) teaches pepsin digestion time can induce changes in collagen molecular fragments. Likewise, combining pepsin with guanidine HCl treatment can affect the products of pepsin digestion. Thus, the issue remains that when various embodiments of the method of claim 43 are carried out, different hydrogels will result, the composition of which cannot be envisioned as the Specification only correlates one specific method to a specific hydrogel with small collagen fragments. It appears the hydrogel should be claimed by virtue of its characteristics as opposed to the process it was obtained. Alternatively, the scope of the process should be commensurate in scope with the guidance in the specification.
Enablement-New Rejection
Claims 36 and 28-42 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The nature of the invention relates to obtaining an extracellular matrix (ECM) from adipose tissue that is free of cells, nucleic acids and lipids.
The claims now require the fibrillin-1 be present in fragments of 10-40 kDa.
The specification teaches obtaining ECM from human adipose using a method that comprises freezing human adipose tissue, slicing the tissue, denaturing the slice of tissue with guanidine HCl, mechanically homogenizing the tissue to lyse the cellular material, contacting the tissue with nucleases, followed by acid/pepsin and dialysis. These steps affect the composition in terms of what proteins remain and the size of their fragments. The specification discusses the small sizes of the collagen fragments but does not teach this size for fibrillin.
Maddox (Journal of Biological Chemistry, vol 264. No. 35, Issue of December is, PP .21381-21385,1989) teaches that fibrillin-1 is a 350 kDa non-collagenous protein. When digested with pepsin, it forms 3 large pepsin-resistant fragments, PF1, PF2 and PF3. Maddox teaches PF1 and PF2 are relatively smaller rod-shaped fragments (95kDa and 50kDa, respectively) and PF3 is a large cluster. See also, Glanville (Journal of Biological Chemistry, Vol. 269, No. 43, Issue of October 28. pp. 26630-26634, 1994). Thus, fibrillin-1 is relatively pepsin resistant, producing only 3 fragments that are larger than 30 kDa.
The specification teaches a method that comprises use of guanidine HCl which mainly denatures globular proteins but at higher concentrations, can partially denature fibrous proteins (collagen and fibrillin, for example). This step will alter the ECM structure. Accordingly, rather than being comprised of large collagen fibers over 100 kDa, the specification teaches the presence of collagen fragments ranging from 10-30 kDa with an average of 20 kDa. The claims, however, require small fragments of fibrillin-1, not collagen.
Thus, it would require undue experimentation to determine how to make a hydrogel composition having small 10-40 kkDa pepsin fragments.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claim(s) 36-38 and 42 is/are rejected under 35 U.S.C. 102(A)(1) and (a)(2) as being anticipated by US 20120264190 (Christman) as evidenced by Brown (2011, Tissue Engineering Part C: Methods, 17, pages 411-421) is withdrawn because Christman did not teach fibrillin fragments ranging from about 10-40kDa.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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