DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/12/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of fulvestrant as the elected one or more therapeutic agent species, inguinal hernia as the elected hernia, and injection as the elected route of administration in the reply filed on 10/11/22024 is acknowledged and maintained.
Priority
This application is a division of U.S. Application No. 17/198,558, filed on March 11, 2021, which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/988,218, filed on March 11, 2020.
Claim Status
Claims 1-3, 7, 14-33 are pending. Claims 4-6 and 8-13 are canceled. Claims 14-15, 17, 18, 19, 26, and 29 are withdrawn. Claims 1-3, 7, 16, 20-25, 27-28, and 30-33 are examined in accordance to the elected species.
Action Summary
Claims 1-3, 7, 16, 20-25, and 27-33 are rejected under 35 U.S.C. 103 as being unpatentable over by Zhao PNAS, vol. 115, No. 44, pages E10427–E10436, October 16, 2018 in view of Roberson (British Journal of Cancer (2001) 85(Suppl 2), 11–14) are maintained, but modified and revisited.
Specification
The disclosure is objected to because as containing improper and potentially argumentative language. Specifically, the tern “novel” as used in paragraph [0083] and other paragraphs in the specification constitutes a conclusionary statement regarding patentability, which is a legal determination reserved for the Office. Appropriate correction is required.
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 non-obviousness.
Claims 1-3, 7, 16, 20-25, and 27-33 are rejected under 35 U.S.C. 103 as being unpatentable over by Zhao PNAS, vol. 115, No. 44, pages E10427–E10436, October 16, 2018 in view of Roberson (British Journal of Cancer (2001) 85(Suppl 2), 11–14).
Zhao teaches that inguinal hernia formation and progression are driven by estrogen-mediated fibrosis and muscle atrophy in lower abdominal muscle (LAM) tissue. Specifically, Zhao teaches that conversion of testosterone to estradiol (E2) via aromatase in LAM tissue causes intense fibrosis, leading to muscle atrophy and inguinal hernia. (See Abstract; pages E10427, left column first paragraph.) Moreover, Zhao teaches that estradiol acts through Erα in LAM fibroblast to induce fibroblast proliferative and extracellular matrix deposition, which replaces myocytes and results in hernia formation. (See pages E10427, left col. First paragraph; E10431, left col. “Discussion”). Importantly, Zhao demonstrates that inhibition of estrogen production using an aromatase inhibitor (letrozole) restores hormone levels, prevents fibrosis and myocytes atrophy, and prevents hernia formation. (See E10429, Fig. 3A-I; pages E10430, left col. First paragraph.) Moreover, Zhao teaches hernia size increases progressively over time in the model. (See page E10429, Fig. 2B and accompanying text.) The administration of the aromatase inhibitor (letrozole) was administered subcutaneously (reading on by injection) to (See page E10430, left column, second paragraph; Abstract; and page 10435, left column, second paragraph.) Furthermore, Zhao teaches age is a significant risk factor for inguinal hernia formation in men with a striking increase in incidence after the age of 55 y. By the time they reach 75 y of age, nearly 50% of men will develop inguinal hernia. Indirect inguinal hernia, which comprises 70% of all hernias, peaks between the ages of 70 and 79 y in men. It is a disease of primarily elderly men. (See second paragraph of the right column of page E10727.) Men are males.
Because Zhao establishes that hernia formation results from ongoing, estrogen-driven fibrotic remodeling and muscle atrophy, a person of ordinary skill in the art would have understood that these are dynamic and biological reversible processes. Accordingly, inhibition of estrogen signaling would have been reasonably expected to arrest further fibrotic progression, and reduce the underlying fibrosis and tissue weakening. Thereby, reducing the size and severity of an exhibiting hernia, in this case inguinal hernia, in view of Zhao’s teaching that hernia size increases over time as fibrosis progresses. (See page E10429, Fig. 2B; page E10431, left col.)
Zhao does not expressly teach ICI 182780 (fulvestrant).
Robertson teaches fulvestrant (ICI182,780) is a selective estrogen receptor degrader (SERD) that blocks estrogen signaling by degrading the estrogen receptor and it is used as an anti-estrogen therapeutic. (See page 11-14.)
it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer an intramuscular injection of ICI 182780 (fulvestrant) as an alternative treatment for inguinal (scrotal) hernia or substitute letrozole as the aromatase inhibition with fulvestrant for reversing inguinal (scrotal) hernia, or administer both as a combination for reversing inguinal hernia. One would have been motivated to do so, because both letrozole and fulvestrant target same pathogenic pathway (estrogen signaling), and reduce estrogenic activity, albeit through different mechanisms (inhibition of estrogen vs. receptor degradation). Given Zhao’s explicit teaching that estrogen signaling via Erα is the causal driver of fibrosis and hernia formation, a person of ordinary skill in the art would have expected that directly inhibiting the estrogen receptor using SERD such as fulvestrant would achieve the same therapeutic objective of reducing estrogen mediated fibrosis. (See page 10431, left col.; Fig 4N-Q showing ER antagonism suppresses estrogen-responsive genes.)
With respect to limitation of claim 16 (surgery), Zhao teaches that hernia development occurs over time and is associated with progressive fibrosis and muscle degeneration, which continues unless estrogen signaling is inhibited. (See page E10429, Fig. 2A-B; pages 10431, left col.) Zhao also teaches inguinal hernia is a common malady in elderly men, and hernia repair is the most commonly performed general surgical procedure in the United States. (See first paragraph of the left column of page E10436.) Because this underlying pathology is ongoing and not limited to a single timepoint, administration of anti-estrogen therapy before surgery (to prevent or reduce progression), during surgery (e.g., perioperative management), and/or after surgery (to prevent recurrence) represents routine optimization and predictable clinical application of a therapy, directed to the underlying disease metabolism
With respect to the recitation that the hernia is “reduced in size” or to a particular size (e.g., less than or equal to 150 mm2) reflects the degree of therapeutic response achieved. Zhao teaches that hernia size increases as fibrosis progresses, and inhibition of estrogen signaling prevents the underlying fibrosis. Thus, reduction in fibrosis would have been expected to reduce hernia size as a predictable consequence of treating the underlying pathology. (See page E10429, Fig.2B; page E10430, left col.) Optimization of treatment conditions to achieve a particular degree of size reduction would have been within the skill in the art.
Affidavit/Declaration
The Affidavit by Serdar E Bulun under 37 CFR 1.132 filed 03/12/2026 is insufficient to overcome the rejection of claims 1-3, 7, 16, 20-25, 27-28, and 30-33.
Applicant’s Declarant traverses the rejection and submit a Declaration asserting that (i) Zhao does not teach reversal of inguinal hernia, (ii) the inventors did not believe reversal was possible at the time of the Zhao publication, and (iii) Robertson does not provide motivation to use fulvestrant for treating or reversing hernia.
With respect to the argument (I), Zhao teaches clearly teaches the underlying mechanism of hernia. Zhao teaches that inguinal hernia formation and progression are driven by estrogen-mediated fibrosis and myocyte atrophy in lower abdominal muscle (LAM) tissue. Specifically, Zhao discloses that conversion of testosterone to estradiol (E2) via aromatase “cause intense fibrosis, leading to muscle atrophy and inguinal hernia.” (See Abstract; pages E10427, left col.) Zhao further teaches that estradiol acts through Erα in LAM fibroblast to induce fibroblast proliferation and extracellular matrix deposition, resulting in progressive fibrosis and weakening of the abdominal wall. (See page E10427, left column; page E10431, Discussion.) Importantly, Zhao demonstrates that inhibition of estrogen production using an aromatase inhibitor (letrozole) restores hormone balance, prevent fibrosis and myocyte atrophy, and prevents hernia formation. (See page E10429Fig. 3A-I; page E10430, left column.)
With respect to (ii), Zhao identifies hernia formation as the result of ongoing, hormone-driven pathological process, namely estrogen-mediated fibrosis and tissue remodeling. Because this process involves fibroblast proliferation, extracellular matrix deposition, and muscle atrophy, it represents a dynamic biological condition rather than a fixed structural defect. Accordingly, a person of ordinary skill in the art would have reasonably expected that inhibition of estrogen signaling would arrest further progression of fibrosis, and reduce the underlying fibrotic pathology. Thus, even in the absence of an explicit disclosure of “reversal,” the claimed outcome represents a predictable consequence of treating the underlying disease mechanism identified in Zhao.
With respect to (iii), Robertson teaches that fulvestrant (ICI18,780) is a selective estrogen receptor degrader (SED) that inhibits estrogen signaling be degrading the estrogen receptor. Zhao teaches that estrogen signaling via Erα is the primary driver of fibrosis and hernia formation, and further demonstrates that ER antagonism (including ICI 1982,780) suppresses estrogen-responsive gene expression in LAM fibroblast. (See Fig. 4N-Q; pages E10431.) Accordingly, a person of ordinary skill in the art would have been expected to use fulvestrant as an alternative or complementary means of inhibiting the same estrogen-driven pathway identified in Zhao, since aromatase inhibitor reduce estrogen production, and SERDs (e.g., fulvestrant) block estrogen receptor signaling. Both approaches target the same pathogenic mechanism and would have been expected to achieve the same therapeutic objective.
Applicant’s Declarant asserts that the inventors did not believe hernia reversal was possible at the time of Zhao publication. (See Paragraph 6 of the Declaration.). However, such statements reflect subjective beliefs and are not controlling. Obviousness is evaluated from the perspective of a person of ordinary skill in the art, the inventors. The fact that the inventors may not have recognized or appreciated the potential for reversal does not negate what would have been reasonably expected in view of the prior art. As discussed above, Zhao provides objective teachings that estrogen signaling drives fibrosis and hernia formation, this process is biologically active and ongoing, and inhibition of estrogen signaling alters this pathology. These teachings support a reasonably expectation that targeting the pathway would reduce disease severity, including hernia size.
Applicant’s Declarant asserts that reversal was not believed to be possible. However, Applicant’s own specification demonstrates that hernia size can be reduced pharmacologically. For example, the specification discloses that “hernia volume was significantly decreased” following treatment, and the reduction remained suppressed over time. (See Examples.) This evidence demonstrates that the disease process is not irreversible, and hernia severity is responsive to pharmacological treatment. Accordingly, Applicant’s own disclosure contradicts the assertion the assertion that reversal or reduction was not reasonably expected.
Applicant’s Declaration further asserts that few researchers were working in this area.
(See paragraphs 7-8). However, the lack of widespread research or recognition does not establish nonobviousness, particularly where, as here, the prior art clearly teaches the underlying disease mechanism, and methods for modulating that mechanism. Such arguments are not commensurate in scope with the claimed invention and do not outweigh the strong evidence of obviousness.
Applicant’s Declaration argues that Robertson is not relevant because it relates to breast cancer. This argument is not persuasive. Robertson is relied upon not for the disease context, but for the teaching of fulvestrant as an anti-estrogen therapeutic (SERD) that inhibits estrogen signaling. Because Zhao identifies estrogen signaling as the causative mechanism of hernia formation, a person of ordinary skill in the art would have recognized fulvestrant as a suitable agent to target that pathway.
In Conclusion, for the reasons set forth above, Zhao teaches the underlying mechanism of hernia formation and progression, Robertson teaches an alternative means of inhibiting that mechanism, and the combination provides a reasonable expectation of reducing hernia severity, including size. Accordingly, the rejection is maintained.
Applicant’s argument and Response the Applicant’s argument
Acknowledgement is made of the receipt and entry of Applicant’s argument filed on March 12, 2026.
Applicant relies on the Bulun Declaration to assert that Zhao does not teach or suggest reversal of hernial and that such reversal was not believed possible at the time. These arguments have been fully addressed above in the section responding to the Declaration and are incorporated herein by reference. To the extent Applicant reiterates these positions in the remarks, they are not persuasive for the reasons previously discussed.
Applicant argues that Zhao id directed only to preventive hernia formation and fails to teach reversing a hernia. This argument is not persuasive. Zhao does not merely disclose a prophylactic effect, but rather identifies the underlying biological mechanism of hernia formation, namely estrogen-drive fibrosis and muscle atrophy in LAM tissue. Zhao further demonstrates that inhibition of estrogen signaling alters this pathological process. Because Zhao teaches that hernia formation is the result of an ongoing hormone-drive fibrotic process, a person of ordinary skill in the art would have reasonably expected that inhibition of this pathway would not only prevent further progression, but also reduce the severity of the condition, including hernia size.
Applicant argues that Robertson is irrelevant because it relates to breast cancer and does not disclose treating or reversing hernia. This argument is not persuasive. Robertson is not relied upon for the disease being treated, but for treating fulvestrant as anti-estrogen therapeutic (SERD) that inhibits estrogen receptor signaling. Zhao expressly teaches that estrogen signaling via Erα is the causal driver of fibrosis and hernia formation. Accordingly, a person of ordinary skill in the art would have been motivated to use fulsetrant as an alternative means of targeting the same pathway identified in Zhao, since aromatase inhibition reduces estrogen production, and SERDs block estrogen receptor signaling. The substitution of one known means of inhibiting estrogen signaling for another represents a predictable variation.
Applicant argues that the prior art fails to teach reversing a hernia in a male subject. This argument is not persuasive. Zho explicitly teaches that inguinal hernia formation is prevalent in male subjects, including the experimental and its relevance to human physiology. (See Discussion of male mice and incidence in men.) Accordingly, the limitation of a male subject does not distinguish over Zhao, as the reference is directly concerned with hernia formation in males.
Applicant asserts that the claimed methods exhibit unexpected results, including reversal of severe hernias and faster therapeutic effects. This argument is not persuasive. To be accorded substantial weight, evidence of unexpected results must be commensurate in scope with the claims, and demonstrate a different in kind, not merely degree. Here, the claims broadly encompass methods of inhibiting estrogen signaling to treat hernia, while the alleged results are limited to particular embodiments and treatment conditions. Moreover, Zhao teaches that hernia formation is driven by estrogen-mediated fibrosis and that inhibition of this pathway alters the disease process. As such, reduction in hernia severity is a predictable outcome of targeting the identified mechanism. Accordingly, the asserted results are considered to be expected consequence of the prior art teachings, or at most a difference in degree, and do not outweigh the strong evidence of obviousness.
Applicant argues that the claimed invention satisfies a long-felt but unmet need and that few researchers were working in this area. These arguments are not persuasive. The existence of a need or limited research activity does not overcome a prima facie case of obviousness where, as here, the prior art provides a clear identification of the disease mechanism, and method for modulating that mechanism. Further, the asserted evidence is not commensurate in scope with the claims and lacks sufficient objective support to outweigh the teachings of the prior art.
Applicant asserts the newly added claims 30-33 are allowed. The recitation that the hernia is “reduced in size” or reduced to a specific size reflects the degree of therapeutic response achieved. Az Zhao teaches that hernia size increases due to progressive fibrosis, inhibition of the underlying estrogen-driven pathway would have been expected to reduce fibrosis and thereby reduce hernia size as a predictable result. Optimization of treatment conditions to achieve a particular size reduction would have been within the ordinary sill in the art.
Conclusion
Claims 1-3, 7, 16, 20-25, 27-28, and 30-33 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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