DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3, 2025 has been entered.
Claims 1-2,4-18, and 53 are under examination.
The examiner has carefully considered applicants’ arguments that the prior art does not expressly teach a method of repairing a ligament, tendon, or cartilage using a non-viable amniotic membrane that releases endogenous tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), hepatocyte growth factor (HGF), transforming growth factor-beta 1 (TGF-β1) and releases only low levels of TNF-α after being applied to the portion of the ligament, tendon or cartilage. The examiner found applicants’ arguments to be persuasive because the examiner agreed with applicants that one would not have been motivated to have combined the teachings of Hariri with Bhatia because Hariri already teaches a successful method of amniotic membrane preservation and would not need to incorporate the preservation method of Bhatia.
The examiner conducted additional searching and discovered a reference recently published by Drs. Beekman and Epitropoulos that teaches that there are significant differences in the factors/proteins released when comparing cryopreserved placental membranes and placental membranes composed of dead cells. Thus, examiner has come to the conclusion that the cryopreserved amniotic membranes with living cells mentioned in the embodiments and working examples in the instant specification do not necessarily release the same endogenous factors/proteins as amniotic membranes composed of all dead cells.
Although examiner has decided to withdrawn the former art rejections, the examiner is now putting forth a written description rejection because the release of TIMP-2, HGF, TGF-β1, etc. is shown as occurring only in cryopreserved samples containing living cells in applicants’ specification. There is no working example provided that shows that these factors are released by the placental membranes with no viable cells.
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 1-2,4-18, and 53 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. The instant claims recite a method of repairing a ligament, tendon, cartilage, in need of repair, the method comprising applying a product comprising an amniotic membrane to at least a portion of the ligament, tendon, or cartilage, wherein the amniotic membrane comprise an epithelial cell layer, a basement layer, and a stromal layer, wherein the product does not include a chorionic membrane, wherein the product does not contain viable cells, wherein the amniotic membrane comprises less than 12.5 pg/cm2 endogenous TNF-α, and wherein the amniotic membrane releases endogenous tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), hepatocyte growth factor (HGF), and transforming growth factor-beta 1 (TGF-β1) after being applied to the portion of the ligament, tendon, or cartilage.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
The claim recites that an amniotic membrane without viable cells comprising less than 12.5 pg/cm2 endogenous TNF-alpha and capable of releasing endogenous tissue inhibitor of matrix metalloproteinase 2, (TIMP-2), hepatocyte growth factor (HGF), transforming growth factor (TGF-beta1) can be administered to ligament, tendon, or cartilage to repair/treat those sites.
However, the working examples in the specification focus on embodiments in which the amniotic and chorionic membranes are cryopreserved in a manner in which some cells present in the membranes remain viable. Example 3 of applicants’ specification details that amnion and chorionic membranes are first refrigerated at 2-8°C for 30 to 60 minutes before freezing at -80°C (Example 3 of the instant Specification). Example 6 and Table 1 and Table 2 of applicants’ specification mention that these amniotic and chorionic membranes have a high viability of certain therapeutic cells meaning that they have living cells. In regards to these amniotic membranes, Table 12 details that the cryopreserved amniotic membranes with the viable cells produce the following proteins: TIMP2, HGF, TGF-beta1, matrix metalloproteinase 2 (Example 19, Table 12 of the instant Specification). The Placental Factors section states that the cryopreserved amniotic membranes with viable cells secrete low amounts of TNF-alpha. The specification does not establish that an amniotic membrane with non-viable cells will release amounts of less than 12.5 pg/cm2 of endogenous TNF-alpha. Non-viable amniotic membranes are only mentioned in a few of the embodiments and these minor embodiments are not associated with the raw protein data that was collected in the working examples for the cryopreserved amniotic membranes with viable cells. Example 21 states that IGF-1 is produced by cryopreserved amniotic membranes with viable cells but does not state that IGF-1 Is also present in the amniotic membranes with non-viable cells. Applicants’ specification focuses on how these factors are present in cryopreserved amniotic membrane with viable cells, not amniotic membranes with dead cells. Furthermore, there is no support in the specification that amniotic membranes with living or dead cells have endogenous TNF-alpha levels that are less than 12.5 pg/cm2 or 6.25 pg.cm2.
Dr. Beckman’s and Dr. Epitropoulos’s Article of October 2, 2025 discusses the differences in structure, function, and endogenous factors between cryopreserved amniotic membranes and dehydrated amniotic membranes with non-living cells. Dr. Beckman discusses that cryopreserved membranes retain both quantity and potency of various endogenous factors. However, dehydrated and dead amniotic membranes often experience degeneration of their endogenous factors. Dr. Beckman uses HC-HA/PTX3 as an example. In cryopreserved amniotic membranes, HC-HA/PTX3 is preserved. However, this factor becomes degraded in dehydrated/dead amniotic membranes.
Dr. Epitropoulos states,…”while dehydrated amniotic membranes (containing dead cells) offer advantages such as longer shelf life and greater cost-effectiveness, cryopreserved amniotic membranes have proven particularly valuable in treating more complex cases, ocular surface diseases and neurotrophic keratitis due to their enhanced regenerative and anti-inflammatory properties.” This is clearly stating that dehydrated amniotic membranes with dead cells can have a different endogenous factor profile compared to amniotic membranes that were cryopreserved.
Conclusion: The working examples of the specification only support the release of TIMP-2, HGF, TGF-β1 by cryopreserved amniotic membranes containing viable cells and that cryopreserved amniotic membranes with living cells release low amounts of the inflammatory factor TNF-alpha. There is no evidence presented in the specification that amniotic membranes with dead cells have the same endogenous factor profile as cryopreserved amniotic membranes with living cells. Furthermore, the reference recently written by Dr. Beekman and Dr. Epitropoulos states that amniotic membranes with dead cells are more likely to have degraded/non-viable endogenous factors. Thus, one cannot conclude that cryopreserved amniotic membranes with living cells have the same endogenous factor profile as amniotic membranes with no living cells.
Conclusion
All clams stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638