DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/10/2025 has been entered.
Claim Status
As of the Final Office Action mailed 8/8/2025, claims 1-12, 14-19, 21-22, 24-27 were pending.
In Applicant's Response filed on 11/10/2025, claim 10 was amended.
As such, claims 1-12, 14-19, 21-22, 24-27 are pending and have been examined herein.
Please note that this action has been made FINAL.
Maintained Rejections
Applicant’s arguments regarding the rejection of record of claim 10 under 35 USC § 112(a) for failing to comply with the enablement requirement has been fully considered but is not persuasive. Thus, the rejection is maintained and recast below. Response to arguments will follow the rejection.
Applicant’s arguments regarding the rejection of record of claims 11-12, 14, 17-19, and 21 under 35 USC § 103 as being unpatentable over Taghizadeh et al (US 8967512 B1, 19 Nov 2014; Published 3 March 2015; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015) has been fully considered but is not persuasive. Thus, the rejection is maintained. Response to arguments will follow the rejection.
Applicant’s arguments regarding the rejection of record of claims 15-16 under 35 USC § 103 as being unpatentable over Taghizadeh et al (US 8967512 B1, 19 Nov 2014; Published 3 March 2015; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015) as applied to claims 11-12, 14, 17-19, and 21 above, and further in view of Morse et al (US11235007B2, 18 Oct 2018; Published 1 Feb 2022) has been fully considered but is not persuasive. Thus, the rejection is maintained. Response to arguments will follow the rejection.
Applicant’s arguments regarding the rejection of record of claims 24-25 under 35 USC § 103 as being unpatentable over Taghizadeh et al (US 8967512 B1, 19 Nov 2014; Published 3 March 2015; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015; previously cited) as applied to claims 11-12, 14, 17-19, and 21 above, and further in view of Daniel et al (US 2018/0311283 A1, 27 June 2016; Published 1 Nov 2018; previously cited) has been fully considered but is not persuasive. Thus, the rejection is maintained. Response to arguments will follow the rejection.
Applicant’s arguments regarding the rejection of record of claims 11-12, 14, 17-19, and 21 under 35 USC § 103 as being unpatentable over Kim et al () in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015; previously cited) has been fully considered but is not persuasive. Thus, the rejection is maintained. Response to arguments will follow the rejection.
Claim Rejections - 35 USC § 112(a)
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.
Claim 10 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 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. Please note that while Applicant has amended claim 10 to include “intracorporeal injection” as the mode of administration, this amendment does not change the substantive issues with the method as claimed under 112(a) enablement. For this reason, the rejection has been maintained and recast below (modified to include the new limitation).
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Claim 10 is directed to a method for reducing size of a Peyronie’s disease plaque in a human subject in need thereof comprising: (a) contacting the Peyronie’s disease plaque with a predetermined volume of the composition of claim 1.
Nature of the invention:
A method for reducing size of a Peyronie’s disease plaque in a human subject in need thereof comprising: (a) contacting the Peyronie’s disease plaque with a predetermined volume of the composition of claim 1.
The state of the prior art:
The state of the prior art for treating Peyronie’s disease in patients in need via intracorporeal injection of umbilical cord filtrate was unpredictable before the effective filing date of the claimed invention.
The breadth of the claims:
The claims encompass a method for treating Peyronie’s disease by contacting a Peyronie’s disease plaque with a predetermined volume of an aqueous umbilical cord filtrate containing various components such as IL-1ra, IGFBP-1, and TIMP-1.
The level of skill in the art:
The level of skill is high that requires a researcher with a PhD degree.
The working examples and guidance provided:
The specification fails to provide any working examples in which any aqueous human umbilical cord filtrate is administered via any administration route to a patient with Peyronie’s disease or Peyronie’s disease plaque. Please note that Fig. 2 of the instant specification does disclose concentration profiles of various components (hyaluronic acid, fibronectin, IGFBP-1, sGAGs, IL-1ra, HGF, TIMP-1 and aggrecan) in an aqueous human umbilical cord filtrate.
The unpredictable nature of the art:
Treating Peyronie’s disease:
Post-dated Mayo Clinic (“Peyronie’s disease”, 27 March 2024; Retrieved from the Internet 6 March 2025; previously cited) states that treatment for Peyronie’s disease depends on how long it has been since symptoms began and whether one is in the acute or chronic phase of Peyronie’s disease (“Treatment” para 1). If a person is in the acute phase, treatments include traction therapy and medicines given by mouth or shots (“Acute phase treatment” para 1). It indicates that there is variability in the success of treatments currently known for the acute phase (same para). During the chronic phase, treatment choice includes watchful waiting where the condition is monitored closely, injections or shots into the scar tissue, traction therapy, or surgery, all of which can be done alone or combined with other treatments depending on the person/severity (“Chronic phase treatment”, para 1). It also teaches that in some people medicines injected directly into the scar tissue on the penis might reduce curving and pain linked with Peyronie’s disease (“Medications” para 1). This shows the various treatment options for Peyronie’s disease and that treatment options depend on the severity of the Peyronie’s disease and there is no currently known treatment that is the “end-all, be-all” for Peyronie’s disease.
Post-dated Babu et al (F1000Res. 2020 May 20;9:F1000; previously cited) teaches that the most accepted pathophysiological etiology of PD is that of microtrauma (“Basic science” para 1). This results from repeated injury resulting in an inflammatory response that promotes the formation of fibrous plaques through mediators such as TGF-β (same para). There are very few studies that are able to show a clear correlation between the histological findings of trauma and Peyronie’s plaques in human histological specimens (same para). The reference also teaches that there is currently limited evidence for the clinical use of stem cells in PD, with all studies restricted to rat models (“Stem cell therapy” para 1). Furthermore, no oral pharmacotherapy is recommended by the American Urological Association (AUA) or the International Consortium of Sexual Medicine (ICSM) because of the lack of robust evidence (“Pharmacotherapy” para 1). The reference further discusses current intralesional injection therapies such as CCH. A randomized study comparing CCH, modelling, and vacuum therapy to CCH and vacuum therapy alone did not show any statistically significant difference between the two groups in terms of curvature improvement or patient-reported outcome measures (“Intralesional injection therapy” para 3). While CCH has clear robust RCT data showing definitive benefit in patients with PD and a penile curvature between 30° and 90, it is clear that the degree of curvature improvement is not as significant as is seen with surgery (“Intralesional injection therapy” para 7-8). The reference concludes that while multiple researchers have attempted to look into the efficacy of oral therapies for PD, it is conceded that there is still no evidence to support their use as first-line treatments in either the acute or the chronic phases. It also states that intralesional treatments with modelling are demonstrating notable promise in treating PD non-surgically and at an earlier stage in the disease process, and while CCH outcomes and safety are supported by a large body of published evidence, the ideal treatment regime is still not clear, thereby making the outcomes difficult to assess (Conclusion, para 1-2). While IFN α-2B shows a small improvement in curvature with a smaller cohort of patients in comparison to IMPRESS I and II, and the results have not been reproduced for over 10 years and there has been no further robust research in other injectable intralesional therapies (same paras).
Post-dated Farrell et al (Transl Androl Urol. 2020 Mar;9(Suppl 2):S269-S283; previously cited) discusses minimally invasive therapies for Peyronie’s disease (title). Specifically, the reference teaches that intralesional injections, such as CCH, result in statistically significant improvements in penile curvature (“Intralesional injection” last para). Data suggests that IFN-α2b and verapamil may also improve penile pain (same para). Although a statistically significant improvement in curvature has been consistently described with intralesional injections, a mean curvature reduction of <20° may not be considered clinically meaningful by many patients, particularly those with more severe deformity, and the timing of administration (acute vs. chronic phase) and patient characteristics (calcification, direction of curvature, indentation deformity) that optimize outcomes remains unclear.
The extremely broad scope of the claims and lack of guidance in the specification exacerbates a highly unpredictable art. While the results presented in the art do not necessarily preclude Applicant’s hypothesis, they certainly fail to support it in its totality that aqueous umbilical cord filtrate can reduce Peyronie’s disease plaques on its own. Applicants do not provide the details of how one of ordinary skill would reasonably administer the aqueous umbilical cord filtrate as instantly claimed to a person and assess the effect of the administered compound on the reduction of a Peyronie’s disease plaque nor is there a reduction to practice the instant method. Consequently, the prior and post-filling art, when combined with the lack of any disclosed direct experimental test of Applicant’s hypothesis, shows that one of ordinary skill would have no basis to reasonably predict or conclude that administration of an aqueous umbilical cord filtrate to a patient with Peyronie’s disease would result in tangible effects (reduction of Peyronie’s disease plaque) as instantly claimed. Though not controlling, the lack of working examples is, nevertheless, a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of 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 Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
In essence, the specification merely presents an idea of, and leaves it entirely up to the practitioner to determine how to carry out the claimed method. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph.
Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary:
The specification merely contains a speculative embodiments of the potential of an aqueous umbilical cord filtrate to be used to treat Peyronie’s disease and leaves it entirely up to one of ordinary skill to determine which population or subpopulations of Peyronie’s patients would be able to be treated, which administration route would be appropriate given a variety of factors and unpredictable nature of effective delivery, effective dosages for Peyronie’s disease to be treated in the disease populations, etc. One of ordinary skill in the art could not reasonably take these mere speculative embodiments and immediately apply it in the claimed method of reducing Peyronie’s disease plaque using the aqueous human umbilical cord filtrate as instantly claimed.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would not be able to make and/or use the invention as claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art.
Response to Arguments
Applicant’s arguments have been fully considered but are not persuasive.
Applicant states (p. 9 of Remarks) that because claim 10 has been amended to include a specific administration route, it obviates the above rejection under 112(a).
In response, the examiner disagrees. The specification merely contains a speculative embodiments of the potential of an aqueous umbilical cord filtrate to be used to reduce Peyronie’s disease plaques. In combination with what was known at the time of filing about reducing Peyronie’s disease plaques, one of ordinary skill would have no basis to reasonably predict or conclude that administration of an aqueous umbilical cord filtrate to a patient with Peyronie’s disease would result in tangible effects (reduction of Peyronie’s disease plaque) as instantly claimed. When prophetic examples are described in a manner that is ambiguous or that implies that the results are actual, the adequacy and accuracy of the disclosure may come into question. When such a rejection is made, the applicant should reply with the results of an actual test or example that has been conducted (i.e., actual, empirical evidence within an affidavit or Declaration), or by providing relevant arguments and/or declaration evidence that there is strong reason to believe that the result would be as predicted, being careful not to introduce new matter into the application. See Hoffmann-La Roche, Inc. v. Promega Corp., 323 F.3d. 1354, 1367, 66 USPQ2d 1385, 1394 (Fed. Cir. 2003). To overcome a prima facie case of lack of enablement, applicant must present argument and/or evidence that the disclosure would have enabled one of ordinary skill in the art to make and use the claimed invention at the time of filing. The examiner notes that the Weston Declaration filed 11/10/2025 does not provide empirical evidence that would necessitate dropping the rejection under 112(a). The burden falls on applicant to present persuasive arguments, supported by suitable proofs where necessary, that one skilled in the art would be able to make and use the claimed invention using the application as a guide. In re Brandstadter, 484 F.2d 1395, 1406-07, 179 USPQ 286, 294 (CCPA 1973) (see MPEP 2164). Thus, the rejection is 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 (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 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.
Claim(s) 11-12, 14, 17-19, and 21 remain rejected under 35 U.S.C. 103 as being unpatentable over Taghizadeh et al (US 8967512 B1, 19 Nov 2014; Published 3 March 2015; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015).
Taghizadeh teaches a tissue mincing tool that minces the tissue sample into fragments (see “Summary of the Invention” para 2; see claim 1 of Taghizadeh). The reference teaches a method of mincing the tissue sample comprising automatically, where the tissue sample can be placental or umbilical cord tissue (see claim 19 of Taghizadeh and “Summary of the Invention” para 5) (“(a) providing a human umbilical cord” as in instant claim 11 in-part). The reference also teaches that the tissue can be washed with a buffered salt solution (i.e., isotonic solution) at any stage of the process (“Cell Isolation and Collection Method” paras 1-2) (“(b) washing the human umbilical cord with an isotonic solution” as in instant claim 11 in-part). After the tissue is minced, the undigested/larger chunks of tissue can be removed by filtering the minced tissue to result in a fluid including cells that remain in the collection sterile container (see 2 and 5-6 of “Summary of the Invention”) (“(c) grinding the washed human umbilical cord tissue of step (b) thereby forming ground umbilical cord tissue; (d) separating the ground human umbilical cord tissue of step (c) into a solid retentate and an aqueous human umbilical cord supernatant . . . none of steps (a)-(e) include introduction of exogenous enzymes resulting in exogenous enzymatic degradation/digestion, and before step (d) contacting the ground umbilical cord tissue formed in step (c) with a filter and subsequently filtering the ground umbilical cord tissue to form the solid retentate retained on the filter and the aqueous human umbilical cord supernatant of step (d) that has passed through the filter” as in instant claim 11 in-part; “grinding tool configured to grind and/or mince the washed human umbilical cord is used during step (c) and grinds the washed human umbilical cord at a range of 40 to 200 revolutions per minute (RPM) until the umbilical cord has been fully ground” as in instant claim 12; see para 0056 of the instant specification that describes the tool of Taghizadeh and was incorporated by reference). The tissue is washed with an appropriate sterile solution such as buffered salt solution (i.e., tissue is sterilized) and the method of mincing is performed in a sterile container such that, absent evidence to the contrary, the resulting micronized tissue and filtrate are sterile (col 9, lines 27-31; see claim 1 and 9 of Taghizadeh) (“wherein both the micronized human umbilical cord composition and the aqueous human umbilical cord filtrate are sterile” as in instant claim 18). Once the suspension is then filtered a second time with a single in-bag filter that retain particle larger than about 100 microns or with a filter that retains particles larger than 150-250 microns (col 2, lines 52-60; col 12, lines 40-42) (“(e) filtering the aqueous human umbilical cord supernatant thereby forming an aqueous human umbilical cord filtrate, the aqueous human umbilical cord filtrate having particles from the ground human umbilical cord tissue that are less than 100 microns in diameter therein” as in in instant claim 11 in-part; “wherein the filter has a porosity ranging from 100 to 200 microns” as in instant claim 14).
Taghizadeh differs from the instantly claimed invention in that it does not teach that the resulting aqueous human umbilical cord filtrate contains interleukin-1 receptor antagonist (IL-1ra) present in a concentration ranging from 200 to 40000 pg/mL (related to instant claim 11 in-part).
Jansen teaches a therapeutic placental composition which stimulates and promotes angiogenesis, reduces inflammation, and reduces scar formation (abstract). The placental tissue can be umbilical cord and includes Wharton’s jelly (abstract) (“comprises at least one of Wharton’s jelly” as in instant claim 17). The cryopreserved placental tissue contains therapeutic factors and is depleted of functional immunogenic cells (i.e., would make the composition non-immunogenic) (see claim 1 of Jansen) (“wherein both the micronized human umbilical cord composition and the aqueous human umbilical cord filtrate are non-immunogenic” as in instant claim 19). The reference describes the types and amount of therapeutic factors present in placental compositions (see Table 1 of Jansen). Specifically, it describes that the compositions from four donors contain IL1-ra at a minimum amount of 961.93 pg/mL, a maximum amount of 10,035.52, and a mean amount of 3,568.27 pg/mL (overlaps with “wherein interleukin-1 receptor antagonist (IL-1ra) is present in the aqueous human umbilical cord filtrate at a concentration ranging from 200 to 40000 pg/mL” as in instant claim 11 in-part). It also contains TIMP1 at a minimum amount of 18,739.41 pg/mL, maximum 315,870.53 pg/mL, and an average of 116341.69 pg/mL, as well as IGFBP-1 at a minimum amount of 5022.86 pg/mL, maximum of 1,227,128.50 pg/mL, and an average of 322,596.69 pg/mL (overlaps with “further comprising: tissue inhibitor of metalloproteinase 1 (TIMP-1) at a concentration ranging from 1.0x104 pg/mL to 8.0x105 pg/mL, and insulin growth factor binding protein-1 (IGFBP-1) at a concentration ranging from 6.0x103 pg/mL to 6.0x106 pg/mL” as in instant claim 21).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a filtered aqueous solution from ground human umbilical cord tissue using a mincing tool that maintains sterility as taught by Taghizadeh, where the composition contains IL-1ra at a minimum amount of 961.93 pg/mL as taught by Jansen, to arrive at the instantly claimed invention. As Jansen shows that placental tissue such as umbilical cord contains IGFBP-1, IL-1ra, TIMP-1, and Wharton’s jelly, one of ordinary skill would reasonably expect the filter solution from ground human umbilical cord as taught by Taghizadeh to exhibit a similar content of therapeutic factors such as Wharton’s jelly, IL-1ra, IGFBP-1, and TIMP-1 that advantageously reduces inflammation, stimulates and promotes angiogenesis, and reduces scar formation as taught by the prior art.
Response to Arguments
Applicant’s arguments and the Declaration filed by Dr. Weston (the “Weston Declaration”) regarding the combination of the Taghizadeh and Jansen references have been fully considered but are not persuasive. On p. 11-17 of Remarks, Applicant argues, in sum, that the combination of Taghizadeh and Jansen does not render obvious the concentration of IL-1ra because there supposedly “is no articulated rationale for substituting the concentrations in the chorion retentate of Jasen with the filtrate of Taghizadeh.” The examiner addresses each argument below:
Applicant first argues that the examiner failed to consider express claim elements (umbilical cord filtrate) and did not articulate why one of ordinary skill would find a prima facie case of obviousness from the composition of Jansen and the composition of Taghizadeh. Applicant argues (p. 15-16) that one of ordinary skill would recognize the difference between “filtrate” and “retentate.” Applicant argues that the Weston declaration shows differences in therapeutic factor concentration between UC filtrates and UC retentates in Appendix A (reproduced below) and that there may be a difference of several logs between same factors from the same tissue from retentate versus filtrate. Thus, Applicant argues, that IL-1ra concentration from the retentate from a different tissue cannot be interchangeable with filtrate. Applicant further argues that the Weston declaration attests that one of ordinary skill would recognize that umbilical cord (used in the instant application and chorion (used in the working examples of Jansen) to be different tissues containing different concentrations of factors. The Weston declaration further states that different tissues have different factor profiles, analogizing the different functions/factors present in liver versus kidney with umbilical cord versus other placental tissues (p. 3 of declaration). Applicant further points to Examples 1-2 and 9 of Jansen in which chorionic membrane was digested with dispase or collagenase and argues that exogenous enzymatic digestion alters therapeutic factor concentration (p. 16-18 of Remarks; p.4-5 of the Weston declaration). Applicant argues that the chorion tissue used in these examples inherently contains different therapeutic factors at different concentrations. Applicant (and the Weston declaration) further discuss references Wu et al. and Lim et al. (provided by Applicant) to support this assertion and states that the examiner has not considered that the concentrations in Jansen were altered by the use of dispase and/or collagenase.
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In response, the examiner disagrees. First, the examiner has considered the express terms “filtrate” as recited in the claim. And, as Applicant has conceded in the Remarks filed 11/10/2025, the Taghizadeh reference (as well as the Kim reference discussed below) teaches a method of producing an umbilical cord filtrate as instantly claimed. The Jansen reference was cited to render obvious the presence of Applicant’s instantly claimed therapeutic factors as well as relative concentrations. Although Applicant argues that the method utilized on Jansen is different from Taghizadeh, at least para 70-71 of the Jansen reference states that the placental dispersion, a composition formed by physical mechanical disruption of placental tissue (which can be umbilical cord tissue; see abstract, para 75 of Jansen, and Jansen disclosure throughout), “may be in the form of a homogenate, a blend, a suspension, a colloid, or a solution, among others” (i.e., not limited to the tissue fraction/retentate).
Patents and patent applications are relevant as prior art for all they contain (see MPEP 2123). "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Moreover, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
The examiner previously made the analogy that “the concentration of components in orange juice would necessarily come from the orange it was squeezed from” (see p. 11 of final Office action mailed 8/8/25). This analogy was made to illustrate that the components being claimed (IL-1ra) themselves come from the umbilical cord tissue even if there is some variation in the concentrations. While the appendix from the Weston declaration is appreciated, it does show that both filtrate and retentate contain the same therapeutic factors as instantly claimed (as argued by the examiner). Moreover, while Applicant (and the Weston declaration) argue that there are differences by several logs (HGF and hyaluronic acid) between the concentrations of filtrate and retentate, Applicant has not provided any empirical evidence that the concentration required by the instant invention are critical. Even Applicant’s own instantly claimed concentration ranges differ by, for example, 200 fold (200 pg/mL to 40,000 pg/mL for IL-1ra).
Applicant has also ignored the teachings of Jansen that state that the concentrations of these therapeutic factors can vary significantly. First, para 85 of Jansen states that the placental composition contains therapeutic factors including those that promote angiogenesis, cell proliferation, and epithelialization including HGF, IGFBP1, TIMP1, fibronectin, and IL-1ra (among others). The Jansen reference further states that tables 1-2 (as utilized in the rejection above) and table 5 describe the therapeutic profile of factors and that these factors are present in an amount of about 20% to about 500% of the mean, minimum, or maximum (respectively) of the values set forth in the tables (para 111 of Jansen). The useful placental compositions can have a therapeutic profile as set forth in tables 1-2 and 5 or comprise at least two or more therapeutic factors as noted in said tables (same para). Table 1 states that, across four different donors, IL1-ra was found in a minimum concentration of 961.93 pg/mL, maximum 10035.52 pg/mL, and a mean of 3568.27 pg/mL. Looking at just the minimum concentration, one of ordinary skill would recognize that the minimum concentration of IL-1ra in the composition can vary (based on para 111 of Jansen) between ~192 to ~4810 pg/mL (overlaps with the instantly claimed 200-40,000 pg/mL). Table 5 (composition made from exemplary amniotic tissue) states that IL1-ra was present at a minimum of 7542.74, maximum of 10535.55, and mean of 9039.14 pg/mL. Again, looking at just the minimum, the minimum concentration can vary between ~1509 to ~52,678 pg/mL (still overlapping with the instantly claimed concentration). Taking the teachings of these paragraphs, working examples, and table 2 (describing the specific functions of the therapeutic factors) in combination, one of ordinary skill would recognize prior to the effective filing date that (1) various placental compositions (umbilical cord derived, amnion derived, chorion derived) contain the necessary therapeutic factors claimed, and (2) although specific concentrations may vary depending on donor, tissue source, manner of disruption (enzymatic versus mincing), etc., the composition still maintain therapeutic effects based on the presence of the factors themselves and not their relative concentrations.
The examiner directs Applicant to multiple instances in which the Jansen reference states that the placental composition can be made of various placental tissues, including umbilical cord (see abstract, paras . Based on the disclosure of Jansen, one of ordinary skill would recognize these placental tissues to be interchangeable for each other while maintaining the therapeutic effects and containing the therapeutic factors described in the reference (specifically, IL-1ra, fibronectin, TIMP1, IGFBP-1 as instantly claimed). Otherwise, the Jansen reference would discredit or disparage a particular tissue for the purposes discussed (see MPEP 2123).
The cited Wu reference provided by Applicant discusses a comparison between mesenchymal stem cells derived from the human placenta and umbilical cord. Specifically, the reference analyzed the origin of the tissue-derived MSCs (fetal vs maternal), discussed the differences in proliferation rate between the different tissue derived MSCs, and while exhibiting similar surface marker expression based on ISCT criteria, there were differences in CD106 expression (see Wu disclosure throughout; p. 2-3 and Fig. 1). These cells also demonstrated differences in secretion patterns of certain growth factors and cytokines. The reference concludes that the MSCs from these different tissue sources may be suitable for different clinical applications (angiogenic therapy vs treating premature ovarian aging vs limb ischemia, for example) (see p. 5 of Wu). None of the teachings of Wu are commensurate with the scope of the claims as the instant claims are not drawn to a composition of MSCs from a particular placental source.
Regarding the use of exogenous digestive enzymes, the examiner notes that the Lim reference is related to the effect of dispase on amniotic membrane, which Applicant has argued is fundamentally different from umbilical cord tissue (and subsequent factors derived from said tissue) (i.e., contrary to Applicant’s arguments). Even if we take the Lim reference into account, the Jansen reference both contemplates and recognizes the effects of exogenous enzyme use on placental tissue-derived factor concentrations. The Jansen reference first states that the placental tissue can be “disrupted, for example by mincing, without contacting the placental tissue with a collagenase or similar digestive enzyme. Disrupting the placental tissue without a digestion step is less time consuming than a process that includes a digestion step and provides a minimally manipulated placental composition with a high viability of live cells” (para 102; see also para 104-107). The working examples of Jansen describe obtaining placental compositions by various means including (1) digestion and homogenization, (2) digestion and mincing, and (3) mincing with a mezzaluna (see examples 2-4). Moreover, example 26 of the Jansen reference describes the differences between therapeutic factor concentrations (in this case, VEGF) obtained from minced versus digested compositions (para 320-323). Of note, Jansen states that the results in Fig. 20 “indicate that both minced and digested placental compositions contain VEGF, though minced composition contains a greater quantity for both tested lots. Because minced placental composition is not partially digested in collagenase as placental composition prepared as in Example 2 or Example 3, minced placental composition likely retains a greater quantity of native growth factors and extracellular matrix proteins.” Jansen recognizes the effects of using enzymatic digestion and mincing placental compositions, but provides one of ordinary skill sufficient teachings that (1) either physical or enzymatic disruption can be used to create the placental composition containing therapeutic factors and (2) that enzymatic digestion may alter therapeutic factor concentration and mincing retains a larger quantity of therapeutic factors.
In sum, Applicant seems to be arguing the legal bases and rationales provided by the examiner instead of the objective evidence made of record. Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). As per MPEP 716.01(c), to be of probative value, any objective evidence should be supported by actual proof. Thus, these arguments are not persuasive and the rejection is maintained.
Claim(s) 15-16 remain rejected under 35 U.S.C. 103 as being unpatentable over Taghizadeh et al (US 8967512 B1, 19 Nov 2014; Published 3 March 2015; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015; previously cited) as applied to claims 11-12, 14, 17-19, and 21 above, and further in view of Morse et al (US11235007B2, 18 Oct 2018; Published 1 Feb 2022; previously cited).
The teachings of Taghizadeh and Jansen in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 14 of which claims 15 and 16 depend. The teachings will not be repeated here.
Regarding claim 16, Jansen teaches that placental compositions contains IGFBP-1 at a minimum amount of 5022.86 pg/mL, maximum of 1,227,128.50 pg/mL, and an average of 322,596.69 pg/mL (overlaps with “comprising . . . IGFBP-1 at a concentration ranging from 1500 pg/mL to ~9000 pg/mL” as in instant claim 16 in-part).
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the solid retentate is milled, freeze-dried, or dehydrated to form a micronized human umbilical cord composition (related to claims 15 and 16 in-part).
Morse teaches a composition comprising micronized placental tissue particles (see claim 1 of Morse). The micronized placental tissue particles are dehydrated by chemical dehydration followed by freeze-drying (see col 6 lines 37-45) and have particles from 25 μm to 150 μm (see claims 5 and 8 of Morse) (“wherein the further processing step of the solid retentate is included and is a . . . dehydration process that forms the micronized human umbilical cord composition having particle sizes ranging from greater than 1 μm to less than 300 μm with the particles being polydispersed” as in instant claim 15; “wherein the micronized human umbilical cord composition is a dried micronized human umbilical cord tissue having a particle diameter size ranging from greater than 1 μm to less than 300 μm” as in instant claim 16 in-part). Finally, the reference teaches that the micronized tissue can be used in guided tissue regeneration and enhancing wound healing (see claims 39 and 61 of Morse).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a filtered aqueous solution from ground human umbilical cord tissue as taught by Taghizadeh and Jansen in combination, where the leftover umbilical cord tissue is further processed through dehydration as taught by Morse, to arrive at the instantly claimed invention. As Morse shows that micronized umbilical tissue can be dehydrated, one of ordinary skill would have been motivated to process the leftover umbilical cord tissue of Taghizadeh and Jansen in combination to form micronized particles via dehydration with a reasonable expectation of advantageously having a product that can be used for enhancing wound healing or in guided tissue regeneration as taught by the prior art.
Response to Arguments
On p. 18 of Remarks, Applicant argues that the Morse reference fails to remedy the deficiencies of Taghizadeh and Jansen and Morse discloses micronized placental tissue particles made of amnion and chorion and, thus as argued, does not disclose micronized human umbilical cord composition made by milling, freeze-drying, or dehydration.
In response, the examiner disagrees. Applicant’s own disclosure discusses the application of the Morse reference’s method in the instant claim (see para 59, reproduced below). The U.S. Pat. No. 10,105,398 reference described in the instant specification is an earlier patent of the ‘007 patent (cited herein and in previous Office actions) and both discuss the cryomilling steps to produce micronized placental tissue (reproduced below), which Applicant’s disclosure explicitly states can be used to form micronized tissue. Thus, Applicant’s argument is not persuasive and the rejection is maintained.
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Claim(s) 24-25 remain rejected under 35 U.S.C. 103 as being unpatentable over Taghizadeh et al (US 8967512 B1, 19 Nov 2014; Published 3 Mach 2015; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015; previously cited) as applied to claims 11-12, 14, 17-19, and 21 above, and further in view of Daniel et al (US 2018/0311283 A1, 27 June 2016; Published 1 Nov 2018; previously cited).
The teachings of Taghizadeh and Jansen in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 11 of which claim 24-25 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the umbilical cord composition contains transthyretin in an amount of 600 to 600,000 pg/mL.
Daniel teaches products derived from amniotic fluids and membranes from various tissues of the fetus and placental tissues (para 0074). The product contains proteins such as epidermal growth factor (EGF), transforming growth factor alpha (TGFa), transforming growth factor beta (TGFβ), insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), a tissue inhibitor of metallopeptidase (TIMP), lactoferrin (LF), alpha defensin 1 (HNP1), alpha defensing 2 (HPN2), alpha defensing 3 (HPN3), or interleukin 1A receptor (IL-1Ra) (para 0075) (note that IL1-ra and TIMP are factors required of the instant claims). The proteins within the product can be used for regenerative medicine and wound healing (see para 0007). The reference also teaches that other proteins, including transthyretin, are contained in the product (para 0076; see Table 1). The reference also teaches that the total protein content per volume of product prepared may range from less than about 1 μg/mL to greater than 15 mg/mL of product (i.e., less than about 1,000,000 pg/mL total proteins to 15 mg/mL) (para 0122).
Daniel does not explicitly teach that the product contains transthyretin in an amount of 600 to 600,000 pg/mL, however, it does show that products derived from amniotic fluids and membranes from placental tissue contains transthyretin. Applicant’s instantly claimed 600 to 600,000 pg/mL is a de minimis amount of transthyretin. Given the large range of protein content as described by Daniel, one of ordinary skill in the art would reasonably expect to find some amount of transthyretin in placental tissues, including umbilical cord tissue. Furthermore, general differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05 (II)(A)).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a filtered aqueous solution from ground human umbilical cord tissue as taught by Taghizadeh and Jansen in combination, where the composition contains transthyretin as taught by Daniel, to arrive at the instantly claimed invention. As Daniel shows that fetal and placental tissues such as amniotic membranes and fluids contain transthyretin, one of ordinary skill would reasonably expect the composition of Taghizadeh and Jansen in combination to contain any amount, including 600 to 600000 pg/mL, of transthyretin and advantageously use it for regenerative medicine and wound healing as taught by the prior art.
Response to Arguments
On p. 18 of Remarks, Applicant argues that the Daniels reference discusses proteins found in amniotic fluid and not umbilical cord. Applicant argues that the presence of transthyretin at an undisclosed concentration in amniotic fluid does not render prima facie obvious transthyretin at the instantly claimed concentration from umbilical cord.
In response, the examiner disagrees. First, as stated above, Applicant has not provided any empirical evidence as to the criticality of the concentration of transthyretin as claimed. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (see MPEP 2144.05(II)). Second, the Daniels reference states that the proteins (IL-1ra, TIMP, transthyretin, and others) found in amniotic fluid are released into it from various fetal and maternal placental tissues (see para 74). Solely to rebut Applicant’s argument, the examiner cites to Tisi et al. (J Nutr. 2004 Jul; 134(7):1754-8), which describes the presence of transthyretin (also known as prealbumin) in amniotic fluid. It states that amniotic fluid is crucial to fetal health because it forms a protective sac around the infant that prevents mechanical and thermal shock, possesses antimicrobial activity, assists in acid/base balance, and contains nutritional factors (para 1). A wide range of proteins has been identified in human AF. These proteins (some key proteins found in amniotic fluid associated as a biomarker with fetal outcomes including insulin-like growth factor binding protein-1 (IGF-BP1) and erythropoietin (EPO), prealbumin, and abnormal albumin bands) can enter the amniotic fluid from the maternal uterine tissues, umbilical cord, amniotic fluid cells, fetal urine, meconium, and other fetal secretions that include transudation through fetal skin (para 1 and 3 of Tisi). Thus, based on at least the Daniels reference, one of ordinary skill in the art before the effective filing date of the instant invention would (1) recognize umbilical cord to be part of placental tissues, (2) know that amniotic fluid derives its proteins from placental tissues like umbilical cord, and (3) would expect some amount of transthyretin to be found in at least umbilical cord (especially in consideration of at least evidentiary reference Tisi). Thus, Applicant’s argument is not persuasive and the rejection is maintained.
Claim(s) 1-3 and 5-9 remain rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (US20140295554A1; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; Published 12 Nov 2015; previously cited).
Kim teaches a serum substitute comprising an umbilical cord extract wherein the umbilical cord extract is prepared according to a method, comprising: cutting an umbilical cord; putting the umbilical cord into a buffer; stirring the umbilical cord impregnated in the buffer; and centrifuging a product obtained from the stirring to obtain a supernatant (see claims 4 and 5 of Kim) (“wherein the aqueous human umbilical cord filtrate has not been subjected to exogenous enzymatic digestion” as in instant claim 2). The reference teaches that the buffer can be phosphate buffered saline (PBS) (para 0060) and that based on quantitative analysis, 700 of pg/ml IL-1 ra is a primary ingredients among extracted cytokines (FIG. 12) (“an aqueous human umbilical cord filtrate having interleukin-1 receptor antagonist (IL-1ra) present in the aqueous human umbilical cord filtrate at a concentration ranging from 200-40000 pg/mL” as in instant claim 1 in-part; “wherein the aqueous human umbilical cord filtrate further comprises an isotonic solution” as in instant claim 5; “wherein the isotonic solution is phosphate buffered saline” as in instant claim 6). The collected umbilical cord extract was filtered using a final filter having a diameter of 0.22 um (i.e., would filter out particles greater than 0.22 um) (para 0146) (“composition does not include particulates exceeding 100 um in diameter” as in instant claim 3; “wherein the aqueous human umbilical cord filtrate comprises particles from a human umbilical cord tissue that are less than 100 um in diameter therein” as in instant claim 7).
Kim differs from the instant invention as claimed in that it does not teach that the filtrate contains TIMP-1 at a concentration of 10000-800000 pg/mL, IGFBP-1 at a concentration of 10000-6000000 pg/mL, and at least one of endogenous hyaluronic acid and/or hyaluronan, fibronectin, transthyretin, aggrecan, or a combination thereof.
Jansen teaches a therapeutic placental composition which stimulates and promotes angiogenesis, reduces inflammation, and reduces scar formation (abstract). The placental tissue can be umbilical cord (abstract). The cryopreserved placental tissue contains therapeutic factors and is depleted of functional immunogenic cells (i.e., would make the composition non-immunogenic) (see claim 1 of Jansen) (“wherein both the micronized human umbilical cord composition and the aqueous human umbilical cord filtrate are non-immunogenic” as in instant claim 8). The reference describes the types and amount of therapeutic factors present in placental compositions (see Table 1 of Jansen). Specifically, it describes that the compositions from four donors contains TIMP1 at a minimum amount of 18,739.41 pg/mL, maximum 315,870.53 pg/mL, and an average of 116,341.69 pg/mL, as well as IGFBP-1 at a minimum amount of 5022.86 pg/mL, maximum of 1,227,128.50 pg/mL, and an average of 322,596.69 pg/mL (overlaps with “tissue inhibitor of metalloproteinase 1 (TIMP-1) present in the aqueous human umbilical cord filtrate at a concentration ranging from 1.0x104 pg/mL to 8.0x105 pg/mL, insulin growth factor binding protein-1(IGFBP-1) present in the aqueous human umbilical cord filtrate at a concentration ranging from 1.0x104 pg/mL to 6.0x106 pg/mL” as in instant claim 1 in-part). The reference teaches that the composition also contains therapeutic factors such as fibronectin (para 85) (“and at least one of . . . fibronectin” as in instant claim 1 in-part). Furthermore, the placental composition can be injected through a syringe or needle (para 189) (“A kit comprising a . . . preloaded syringe having the processed human umbilical cord composition of claim 1 therein” as in instant claim 9).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a human umbilical cord tissue extract as taught by Kim, where the composition contains TIMP-1 at a minimum amount of 18,739.41 pg/mL, IGFBP-1 at an average of 322,596.69 pg/mL, and fibronectin as taught by Jansen, to arrive at the instantly claimed invention. As Jansen shows that placental tissue such as umbilical cord contains IGFBP-1, TIMP-1, and fibronectin, one of ordinary skill would reasonably expect an extract from human umbilical cord as taught by Kim to exhibit a similar content of therapeutic factors such as fibronectin, IGFBP-1, and TIMP-1 that advantageously reduces inflammation, stimulates and promotes angiogenesis, and reduces scar formation as taught by the prior art.
Response to Arguments
On p. 21 of Remarks, Applicant argues that the examiner cannot credibly rely on the Kim reference to disclose the claimed amount of IL-1ra because of the discrepancy between para 136 and Fig. 12 of Kim. Applicant argues that para 136 of Kim states that 700 pg/mL of IL-1ra was present in extracted cytokines, however, Fig. 12 shows the y-axis as repeating 240 pg/mL for each data point. Applicant stipulates that it “mak[es] it impossible for anyone reading Kim to determine the accuracy of the disclosed concentration of any of the listed proteins, much less IL-1ra.”
In response, the examiner disagrees. Again, As stated in prior interviews of record, it was agreed upon by both the examiner and supervisory examiner that, regardless of the discrepancies between the 240 pg/mL taught in Fig. 12 and 700 pg/mL taught in para 136, the Kim reference can be credibly relied upon because both values render prima facie obvious Applicant’s instantly claimed range of 200 to 40,000 pg/mL as recited in claim 1 (see Examiner interview conducted 2/20/2025, mailed 2/26/25). Second, as reiterated below, even if the Kim reference was not an issue, the Jansen reference also renders prima facie obvious the concentration of IL-1ra found in placental tissue-based compositions such as umbilical cord (see, e.g., table 1 and 5 of Jansen and above arguments and 103 rejection).
On p. 23 of Remarks, Applicant further argues that the arguments with respect to the rejection of claim 11 applied to Jansen are applicable here as well. Applicant argues that Table 1 of Jansen is related to digested chorion retentate not umbilical cord filtrate and that the examiner has not articulated why one of ordinary skill in the art would substitute the concentrations of Jansen into the umbilical cord filtrate of Kim.
In response, the examiner disagrees. Patents and patent applications are relevant as prior art for all they contain (see MPEP 2123). "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Moreover, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
For Applicant’s convenience, the examiner reiterates the substantive arguments and rationales already stated above for the 103 rejection of claim 11 in view of Taghizadeh and Jansen. The examiner first directs Applicant to multiple instances in which the Jansen reference states that the placental composition can be made of various placental tissues, including umbilical cord (see abstract, paras . Based on the disclosure of Jansen, one of ordinary skill would recognize these placental tissues to be interchangeable for each other while maintaining the therapeutic effects and containing the therapeutic factors described in the reference (specifically, IL-1ra, fibronectin, TIMP1, IGFBP-1 as instantly claimed). Otherwise, the Jansen reference would discredit or disparage a particular tissue for the purposes discussed (see MPEP 2123). Para 85 of Jansen states that the placental composition (which as reiterated above, can be made of various placental tissues like umbilical cord) contains therapeutic factors including those that promote angiogenesis, cell proliferation, and epithelialization including HGF, IGFBP1, TIMP1, fibronectin, and IL-1ra (among others). The Jansen reference further states that tables 1-2 (as utilized in the rejection above) and table 5 describe the therapeutic profile of factors and that these factors are present in an amount of about 20% to about 500% of the mean, minimum, or maximum (respectively) of the values set forth in the tables (para 111 of Jansen). The useful placental compositions can have a therapeutic profile as set forth in tables 1-2 and 5 or comprise at least two or more therapeutic factors as noted in said tables (same para). Table 1 states that, across four different donors, IL1-ra was found in a minimum concentration of 961.93 pg/mL, maximum 10035.52 pg/mL, and a mean of 3568.27 pg/mL. Looking at just the minimum concentration, one of ordinary skill would recognize that the minimum concentration of IL-1ra in the composition can vary (based on para 111 of Jansen) between ~192 to ~4810 pg/mL (overlaps with the instantly claimed 200-40,000 pg/mL). Table 5 (composition made from exemplary amniotic tissue) states that IL1-ra was present at a minimum of 7542.74, maximum of 10535.55, and mean of 9039.14 pg/mL. Again, looking at just the minimum, the minimum concentration can vary between ~1509 to ~52,678 pg/mL (still overlapping with the instantly claimed concentration). Taking the teachings of these paragraphs, working examples, and table 2 (describing the specific functions of the therapeutic factors) in combination, one of ordinary skill would recognize prior to the effective filing date that (1) various placental compositions (umbilical cord derived, amnion derived, chorion derived) contain the necessary therapeutic factors claimed, and (2) although specific concentrations may vary depending on donor, tissue source, manner of disruption (enzymatic versus mincing), etc., the composition still maintain therapeutic effects based on the presence of the factors themselves and not their relative concentrations.
Regarding the use of exogenous digestive enzymes, the Jansen reference both contemplates and recognizes the effects of exogenous enzyme use on placental tissue-derived factor concentrations. The Jansen reference first states that the placental tissue can be “disrupted, for example by mincing, without contacting the placental tissue with a collagenase or similar digestive enzyme. Disrupting the placental tissue without a digestion step is less time consuming than a process that includes a digestion step and provides a minimally manipulated placental composition with a high viability of live cells” (para 102; see also para 104-107). The working examples of Jansen describe obtaining placental compositions by various means including (1) digestion and homogenization, (2) digestion and mincing, and (3) mincing with a mezzaluna (see examples 2-4). Moreover, example 26 of the Jansen reference describes the differences between therapeutic factor concentrations (in this case, VEGF) obtained from minced versus digested compositions (para 320-323). Of note, Jansen states that the results in Fig. 20 “indicate that both minced and digested placental compositions contain VEGF, though minced composition contains a greater quantity for both tested lots. Because minced placental composition is not partially digested in collagenase as placental composition prepared as in Example 2 or Example 3, minced placental composition likely retains a greater quantity of native growth factors and extracellular matrix proteins.” Jansen recognizes the effects of using enzymatic digestion and mincing placental compositions, but provides one of ordinary skill sufficient teachings that (1) either physical or enzymatic disruption can be used to create the placental composition containing therapeutic factors and (2) that enzymatic digestion may alter therapeutic factor concentration and mincing retains a larger quantity of therapeutic factors. Thus, the teachings of Kim and Jansen render prima facie obvious instant claims 1-3 and 5-9 and the rejection is maintained.
Claim(s) 4 and 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (US20140295554A1; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; Published 12 Nov 2015; previously cited) as applied to claims 1-3 and 5-9 above, and further in view of Daniel et al (US 2018/0311283 A1, 27 June 2016; Published 1 Nov 2018; previously cited).
The teachings of Kim and Jansen in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 1 of which claims 4 and 22 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the umbilical cord composition contains transthyretin in an amount of 600 to 600,000 pg/mL.
Daniel teaches products derived from amniotic fluids and membranes from various tissues of the fetus and placental tissues (para 0074). The product contains proteins such as epidermal growth factor (EGF), transforming growth factor alpha (TGFa), transforming growth factor beta (TGFβ), insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), a tissue inhibitor of metallopeptidase (TIMP), lactoferrin (LF), alpha defensin 1 (HNP1), alpha defensing 2 (HPN2), alpha defensing 3 (HPN3), or interleukin 1A receptor (IL-1Ra) (para 0075) (note that IL1-ra and TIMP are factors required of the instant claims). The proteins within the product can be used for regenerative medicine and wound healing (see para 0007). The reference also teaches that other proteins, including transthyretin, are contained in the product (para 0076; see Table 1). The reference also teaches that the total protein content per volume of product prepared may range from less than about 1 μg/mL to greater than 15 mg/mL of product (i.e., less than about 1,000,000 pg/mL total proteins to 15 mg/mL) (para 0122).
Daniel does not explicitly teach that the product contains transthyretin in an amount of 600 to 600,000 pg/mL, however, it does show that products derived from amniotic fluids and membranes from placental tissue contains transthyretin. Applicant’s instantly claimed 600 to 600,000 pg/mL is a de minimis amount of transthyretin. Given the large range of protein content as described by Daniel, one of ordinary skill in the art would reasonably expect to find some amount of transthyretin in placental tissues, including umbilical cord tissue. Furthermore, general differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05 (II)(A)).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a human umbilical cord tissue extract as taught by Kim and Jansen in combination, where the composition contains transthyretin as taught by Daniel, to arrive at the instantly claimed invention. As Daniel shows that fetal and placental tissues such as amniotic membranes and fluids contain transthyretin, one of ordinary skill would reasonably expect the composition of Kim and Jansen in combination to contain any amount, including 600 to 600000 pg/mL, of transthyretin and advantageously use it for regenerative medicine and wound healing as taught by the prior art.
Response to Arguments
On p. 23 of Remarks, Applicant argues that the proteins discussed from Daniel are proteins contained in amniotic fluid not umbilical cord. Applicant further argues that since the examiner admits that Daniel does not teach the claimed concentration, it is insufficient to establish a prima facie case of obviousness.
In response, the examiner disagrees. First, as stated above, Applicant has not provided any empirical evidence as to the criticality of the concentration of transthyretin as claimed. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (see MPEP 2144.05(II)). Second, the Daniels reference states that the proteins (IL-1ra, TIMP, transthyretin, and others) found in amniotic fluid are released into it from various fetal and maternal placental tissues (see para 74). Solely to rebut Applicant’s argument, the examiner cites to Tisi et al. (J Nutr. 2004 Jul; 134(7):1754-8), which describes the presence of transthyretin (also known as prealbumin) in amniotic fluid. It states that amniotic fluid is crucial to fetal health because it forms a protective sac around the infant that prevents mechanical and thermal shock, possesses antimicrobial activity, assists in acid/base balance, and contains nutritional factors (para 1). A wide range of proteins has been identified in human AF. These proteins (some key proteins found in amniotic fluid associated as a biomarker with fetal outcomes including insulin-like growth factor binding protein-1 (IGF-BP1) and erythropoietin (EPO), prealbumin, and abnormal albumin bands) can enter the amniotic fluid from the maternal uterine tissues, umbilical cord, amniotic fluid cells, fetal urine, meconium, and other fetal secretions that include transudation through fetal skin (para 1 and 3 of Tisi). Thus, based on at least the Daniels reference, one of ordinary skill in the art before the effective filing date of the instant invention would (1) recognize umbilical cord to be part of placental tissues, (2) know that amniotic fluid derives its proteins from placental tissues like umbilical cord, and (3) would expect some amount of transthyretin to be found in at least umbilical cord (especially in consideration of at least evidentiary reference Tisi). Thus, Applicant’s argument is not persuasive and the rejection is maintained.
Claim(s) 26 remains rejected under 35 U.S.C. 103 as being unpatentable over Kim et al (US20140295554A1; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; Published 12 Nov 2015; previously cited) as applied to claims 1-3 and 5-9 above, and further in view of Leach et al (WO 2014144505 A2, 14 March 2014; Published 9/18/2014) as evidenced by Ribeiro et al (Stem Cell Res Ther. 2013 Oct 15;4(5):125).
The teachings of Kim and Jansen in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 1 of which claim 26 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach wherein the interleukin-1 receptor antagonist (IL-1ra) present in the aqueous human umbilical cord filtrate at a concentration ranging from 2.0x104 pg/mL to 4.0x104 pg/mL.
Leach teaches a method of generating a solution rich in interleukin-1 receptor antagonist (IL1-ra) comprising (a) obtaining a liquid volume comprising cytokine producing cells by separating cytokine-producing cells from a tissue comprising cytokine- producing cells using a non-centrifugal process; (b) contacting the liquid volume comprising cytokine-producing cells with a solid extraction material; and (c) separating the liquid volume from the solid extraction material to obtain the solution rich in IL-l ra (see claim 1 of Leach). The reference teaches that the non-centrifugal process comprises passing a tissue or tissue fraction comprising cytokine-producing cells through a size exclusion filter (see claim 4 of Leach) and that the solution rich in IL-l ra comprises: (i) interleukin- 1 receptor antagonist (IL-l ra) at a concentration of at least about 10,000 pg/ml, including about 25,000 pg/mL to about 40000 pg/mL (see claim 7 of Leach and Table 1 of Leach) (“wherein the interleukin-1 receptor antagonist (IL-lra) present in the aqueous human umbilical cord filtrate at a concentration ranging from 2.0x104 pg/mL to 4.0x104 pg/mL” as in instant claim 26). Finally, the reference teaches that the increased IL-1ra concentration can be used to create improved methods of treating inflammatory mediated by interleukin-1 (para 006-7).
While Leach does not explicitly teach that the tissue containing cytokine-producing cells is human umbilical cord, evidentiary reference Ribeiro teaches that mesenchymal stem cells are present in fetal tissues such as placenta and umbilical cord (Introduction para 1). It also teaches that MSCs secrete several cytokines that play an important role in the regulation of hematopoiesis, angiogenesis, and in immune and inflammatory response (Introduction para 2). This reference shows that umbilical cord tissue contains MSC that secrete (i.e., produce) cytokines such that one of ordinary skill would readily apply the method of Leach to concentrate IL-1ra from placental sources to obtain Applicant’s instantly claimed concentration.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a human umbilical cord tissue extract as taught by Kim and Jansen in combination, where IL-1ra is present in amounts between 25,000 pg/mL and 40,000 pg/mL as taught by Leach, to arrive at the instantly claimed invention. As Leach shows that solutions from tissues can be enrich with IL-1ra, one of ordinary skill would have been motivated to modify the umbilical cord tissue extract as taught by Kim and Jansen to include a higher concentration of IL-1ra with a reasonable expectation of advantageously improving inflammation mediated by interleukin 1 as taught by the prior art.
Claim(s) 27 remains rejected under 35 U.S.C. 103 as being unpatentable over Taghizadeh et al (US 8967512 B1, 19 Nov 2014; Published 3 March 2015; previously cited) in view of Jansen et al (WO 2015/171142 A1, 7 May 2014; published 12 Nov 2015; previously cited) as applied to claims 11-12, 14, 17-19, and 21 above, and further in view of Leach et al (WO 2014144505 A2, 14 March 2014; Published 9/18/2014).
The teachings of Taghizadeh and Jansen in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 11 of which claim 27 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach wherein the interleukin-1 receptor antagonist (IL-lra) present in the aqueous human umbilical cord filtrate at a concentration ranging from 2.0x104 pg/mL to 4.0x104 pg/mL.
Leach teaches a method of generating a solution rich in interleukin-1 receptor antagonist (IL1-ra) comprising (a) obtaining a liquid volume comprising cytokine producing cells by separating cytokine-producing cells from a tissue comprising cytokine- producing cells using a non-centrifugal process; (b) contacting the liquid volume comprising cytokine-producing cells with a solid extraction material; and (c) separating the liquid volume from the solid extraction material to obtain the solution rich in IL-l ra (see claim 1 of Leach). The reference teaches that the non-centrifugal process comprises passing a tissue or tissue fraction comprising cytokine-producing cells through a size exclusion filter (see claim 4 of Leach) and that the solution rich in IL-l ra comprises: (i) interleukin- 1 receptor antagonist (IL-l ra) at a concentration of at least about 10,000 pg/ml, including about 25,000 pg/mL to about 40000 pg/mL (see claim 7 of Leach and Table 1 of Leach) (“wherein the interleukin-1 receptor antagonist (IL-lra) present in the aqueous human umbilical cord filtrate at a concentration ranging from 2.0x104 pg/mL to 4.0x104 pg/mL” as in instant claim 27). Finally, the reference teaches that the increased IL-1ra concentration can be used to create improved methods of treating inflammatory mediated by interleukin-1 (para 006-7).
While Leach does not explicitly teach that the tissue containing cytokine-producing cells is human umbilical cord, evidentiary reference Ribeiro teaches that mesenchymal stem cells are present in fetal tissues such as placenta and umbilical cord (Introduction para 1). It also teaches that MSCs secrete several cytokines that play an important role in the regulation of hematopoiesis, angiogenesis, and in immune and inflammatory response (Introduction para 2). This reference shows that umbilical cord tissue contains MSC that secrete (i.e., produce) cytokines such that one of ordinary skill would readily apply the method of Leach to concentrate IL-1ra from placental sources to obtain Applicant’s instantly claimed concentration.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a human umbilical cord tissue extract as taught by Taghizadeh and Jansen in combination, where IL-1ra is present in amounts between 25,000 pg/mL and 40,000 pg/mL as taught by Leach, to arrive at the instantly claimed invention. As Leach shows that solutions from tissues can be enrich with IL-1ra, one of ordinary skill would have been motivated to modify the umbilical cord tissue extract as taught by Taghizadeh and Jansen to include a higher concentration of IL-1ra with a reasonable expectation of advantageously improving inflammation mediated by interleukin 1 as taught by the prior art.
Response to Arguments
On p. 19 of Remarks, Applicant argues that Leach expressly teaches the types of tissue utilized in the method taught therefrom and that the concentrations taught in Leach are from different tissues than those instantly claimed. Applicant argues that the examiner has not articulated why one of ordinary skill would substitute the IL-1ra concentration of Leach into Taghizadeh and Jansen. Please note that this response to arguments also relates to later arguments Applicant made regarding the combination of Kim, Jansen, and Leach for the rejection of instant claim 26.
In response, the examiner disagrees. First, patents are relevant as prior art for all that they contain (see MPEP 2123 (I)). "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Taghizadeh and Jansen in combination (as well as Kim and Jansen in combination previously and currently relied upon for the 103 rejection of claim 26) show that umbilical cord tissue-derived products contains IL-1ra, with Jansen showing that the concentration of IL-1ra can vary for numerous reasons previously discussed above. The Leach reference broadly discloses:
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“A tissue comprising cytokine producing cells” as claimed by Leach broadly encompasses all tissues containing cytokine producing cells, not merely the tissues described in the specification of Leach (i.e., preferred embodiments and examples) and the cytokine secreting cells can by MSCs (see Leach disclosure and claims). Evidentiary reference Ribeiro establishes that umbilical cord tissue is a tissue that contains MSCs that secrete cytokines (as described above) and the Jansen reference (which includes umbilical cord tissue as previously discussed; the Kim reference previously discussed also contains similar teachings) states that UC tissues (among other placental tissues) contain cell-derived cytokines and other therapeutic factors (IL-1ra, TIMP1, IGFBP1, etc.) (see at least para 85 of Jansen). As previously argued by the examiner, one of ordinary skill in the art, taking all of these teachings in combination, would recognize that the method of Leach to produce an IL-1ra rich solution from tissues containing cytokine-producing cells could be applied to all tissues containing cytokine producing cells, including umbilical cord tissue (which, as previously established, already contains MSCs, IL-1ra, etc.). Thus, Applicant’s arguments are not persuasive and the rejection is maintained.
Double Patenting
Claims 1-12, 14-19, 21-22, and 24-27 of this application is patentably indistinct from claim 1-19 of Application No. 19/056,248. Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
Response to Arguments
On p. 24 of Remarks, Applicant requests that the double patenting rejection of record be held in abeyance because the ‘248 application is still under prosecution.
In response, the rejections are maintained because the claim of the copending ‘248 application is, as set forth above, exactly the same as the instantly claimed invention. The provisional double patenting rejection will continue to be made by the examiner as long as there are patentably indistinct claims in the applications unless that provisional double patenting rejection is the only rejection remaining in one of the applications (see MPEP § 822). Please note that only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632