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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-7, in the reply filed on 22 December 2025 is acknowledged. The traversal is on the ground(s) that “the Examiner must show that the application claims independent or distinct inventions, as required by both § 121 and the USPTO Rules”. This is not found persuasive because the instant application is national stage application submitted under 35 U.S.C. 371 whereas 35 U.S.C. 121 is applicable to applications filed under 35 U.S.C. 111(a). Applicant is directed to MPEP 801 for an explanation of this distinct. Lack of Unity practice does not require a showing of serious burden, therefore, Applicant’s arguments are not persuasive.
The requirement is still deemed proper and is therefore made FINAL.
Claims 8-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 22 December 2025.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement (IDS) submitted on 04 April 2023 has been considered by the examiner.
Drawings
The drawings, submitted on 06 October 2023, are objected to because they do not comply with 37 CFR 1.84(a)(1) and (l).
(a) Drawings. There are two acceptable categories for presenting drawings in utility and design patent applications.
(1) Black ink. Black and white drawings are normally required. India ink, or its equivalent that secures solid black lines, must be used for drawings
(l) Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction.
Several of the figures do not have solid black lines or text resulting in the inability to interpret the information contained in the figure (see Figure 1 and screenshot below).
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Figure 7A has photographs in which the scale indicator in the photo is completely unreadable as well as having lines which are not solid (see screenshot below).
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Figure 9 is blurry and unreadable (see screenshot below).
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The arrows in the drawing for Figure 10 are not solid black lines.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The claims under examination are directed to treating fibrosis by administering a soluble TGF-β type II receptor. The title should be amended to reflect the invention to which the claims are directed.
The disclosure is objected to because of the following informalities: the description in [00017] appears to contain a typographical error. The text recites “Figures 3A and 2B”, however, based on the paragraph above and below this paragraph, it is believed that the text should be referring to Figures 3A and 3B.
Appropriate correction is required.
The disclosure is objected to because of the following informalities: the text at page 3, last line, and page 6 in [0023] appears to contain a typographical error. The format of
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is not consistent with all other references to sequence identifiers. Paragraph [0023] also does not end in a period.
Appropriate correction is required.
The use of the term Superfrost®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 2 and 7 are objected to because of the following informalities: both claims recite “sequence shown in SEQ ID No”. However, a sequence identifier is not a picture and it does not “show” anything, therefore, this language is not technically correct. The Sequence identifier is a short hand replacement for an actual amino acid or nucleic acid sequence. It would be technically correct to refer to “the amino acid sequence of SEQ ID NO”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inhibition of fibrosis by administering a fusion protein comprising a soluble TGF-β type II receptor having the amino acid sequence of SEQ ID NO:1 bound to a stabilizing agent, does not reasonably provide enablement for treatment of Scleroderma/Systemic Sclerosis (SSc) or for the administration of any and all soluble TGF-β type II receptors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure enables one skilled in the art to make and use the claimed invention in its full scope without resorting to undue experimentation include: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance presented; (3) the presence or absence of working examples; (4) the nature or complexity of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. See In re Wands, 8 USPQ2d. 1400 (Fed. Cir. 1988).
As was found in Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology", Mycogen Plant Sci., Inc. V. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991). In the instant case, the claimed invention involves the effects of complex biochemical molecules on physiological systems. Therefore, the nature of the invention is complex and unpredictable.
Regarding the scope of the claims, hepatic fibrosis is characterized by excessive scarring and extracellular matrix. However, there are many types, causes, and severities of hepatic fibrosis. Not all patients can be successfully treated the same way, depending upon these factors, among others. For a review of this, see Bataller et al. (2005, J. Clin. Invest. 115(2):209-218). The claims are broadly directed to treating fibrosis in a mammal by administering soluble TGF-β type II receptor bound to a stabilizing agent (claim 1) and wherein the fusion protein has at least 85% identity with the amino acid sequence of SEQ ID NO:2 (claim 7).
In contrast to the broad scope of the claims, the amount of detailed guidance and working examples provided by the specification is decidedly narrower. The specification discloses a BLM-induced skin fibrosis model (n=10; mice) (see [00081]) and a BLM-induced pulmonary fibrosis model (n=10; mice)(see [00088]) wherein the mice were administered TβRII-SE/Fc, having the amino acid sequence of SEQ ID NO:2 (wherein the soluble TGF-β type II receptor has the amino acid sequence of SEQ ID NO:1). The specification also discloses induction of hepatic fibrosis by CCl4 in rats (n=10; rats) (see [00096]) wherein the rats were also administered TβRII-SE/Fc (SEQ ID NO: 7) (see [000119]. The specification states that TβRII-SE/Fc administration resulted in a “tendency to decrease in the area of fibrosis” in the skin fibrosis model (see [00037]), a “decreasing trend in the Ashcroft score compared to the vehicle group, suggesting that TβRII-SE/Fc has antifibrotic effects in pulmonary fibrosis” in the pulmonary fibrosis model (see 00041]) and a statistically significant differences in fibrosis score, non-fatty liver disease index, inflammatory cell infiltrate and oval cell hyperplasia in the liver fibrosis model (see [00043]). However, these models are not commensurate in scope with the claims, which are not limited to treatment with TβRII-SE/Fc (SEQ ID NO: 7) and they are also not predictive of all fibrotic conditions or predictive for Scleroderma/Systemic Sclerosis (SSc).
The scope of the claims is broad with respect to the therapeutic agent being administered. Claim 1 does not place any material limitations on the structure of the “soluble TGF-β type II receptor” or on the stabilizing agent of the fusion protein. Claim 7 recites that the fusion protein has at least 85% identity with the amino acid sequence of SEQ ID NO:2. The instant specification discloses a singular therapeutic which was administered which is TβRII-SE/Fc and which consists of the amino acid sequence of SEQ ID NO:2. The specification provides no guidance or direction or examples of any modifications of the soluble TGF-β type II receptor having the amino acid sequence of SEQ ID NO:1, yet the claims encompass any molecule which could be encompassed by the terminology of “soluble TGF-β type II receptor” as well as molecules having up to 15% variation from SEQ ID NO:2.
The amount of detailed guidance and working examples provided by the specification is narrower than the scope of the claims. As stated above, three animal models were used and in each model the protein of SEQ ID NO:7 was administered. However, the claims are not limited to the compound which was used in the examples and there is no guidance or direction on making variants of TβRII-SE/Fc having the amino acid sequence of SEQ ID NO:7.
The state of the art regarding treatment of fibrosis is complicated as is the role of TGF-β in fibrosis. The results of the experiments in the experimental rodent models for BLM-induced fibrosis in the lung and skin only showed a “tendency to decrease in the area of fibrosis” in the skin model (see [00037]) and a suggestion “anti-fibrotic effects in pulmonary fibrosis” in lung model (see 00041]). The results of the experiment for CCl4-induced hepatic fibrosis showed statistically significant results for inhibiting fibrosis. However, these models are not predictive of administration of TβRII-SE/Fc for the treatment of any and all fibrosis in any disease which presents with fibrosis. Bataller et al. teach that while various treatments have been developed for treating liver fibrosis, there are no effective therapies for treating humans based on rodent models (see pages 215-216).
Tsujino et al. (Am. J. Physiol-Lung Cell. Mol. Physio. 312(1): L22-L31, 2017) teaches that TGF-β plays divergent roles in modulating vascular remodeling, inflammation and pulmonary fibrosis in a murine model of scleroderma. Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease and it is characterized in part by fibrosis in the skin, lungs and other internal organs (see page L22, column 1). Tsujino et al. used a Fra-2 transgenic mouse model (Fos-related antigen 2) to study the effects of inhibiting TGF-β as a potential therapeutic for treating fibrosis in SSc (see page L22, column 2) because TGF-β is a major fibrogenic cytokine and a central mediator of fibrosis in multiple organs. Tsuijino et al. treated the Fra-2 transgenic mice with a blocking antibody that targets all TGFβ isoforms. However, while the inhibition of TGF-β reduced the severity of lung vasculopathy, treatment with the TGF-β inhibitor did not ameliorate the severity of pulmonary fibrosis and actually exacerbated lung inflammation (see page L23, column 1, paragraph 2). Therefore, Tsujino et al. teach that inhibition of TGF-β does not treat fibrosis in a murine model of SSc.
Due to the large quantity of experimentation necessary to develop effective
treatments for fibrosis with a fusion protein comprising a soluble TGF-β type II receptor bound to a stabilizing agent or a fusion protein having 85% identity with the amino acid sequence of SEQ ID NO:2, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to specific fibrotic diseases including SSc, the complex nature of the invention, the contradictory state of the prior art, the unpredictability of the effects of TGF-β inhibition on fibrosis, and the breadth of the claims regarding the therapeutic agents being administered, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites “wherein the human has a selected disorder or disease of non-alcoholic steatohepatitis (NASH), Scleroderma / Systemic Sclerosis (SSc), idiopathic pulmonary fibrosis, and Primary biliary cholangitis (PBC)”. However, the claim is unclear and indefinite because while the claim recites that the human has a “selected disorder or disease”, the claim then lists various diseases/disorders and concludes with “and”, which implies that the human has all of the recited diseases/disorders. The claim may be attempting to use Markush language, which requires a closed group and the use of “and” but the claim failed to use the phrasing of “selected from the group consisting of”. As no Markush language is present, the claim could be corrected by amending “and” to “or”. Alternatively, the claim could recite Markush language as indicated above.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by U.S. Pat. Pub. 2019/0112352 (Romo et al.).
Romo et al. teach an isoform of TGF-β receptor II which is a soluble receptor and has the amino acid sequence of SEQ ID NO:1, which is identical to that of the instant application (SEQ ID NO:1). Romo et al. also teach a fusion protein of the soluble TGF-β receptor II protein with a stabilizing agent (Fc of an immunoglobulin) which has the amino acid sequence of SEQ ID NO:2 (see [0015]). The amino acid sequence of SEQ ID NO:2 of Romo et al. has one amino acid difference from that of SEQ ID NO:2 at position 136 (relative to the amino acid sequence of the instant application). Therefore, Romo et al. teach a fusion protein comprising a soluble TGF-β type II receptor bound to a stabilizing agent (claim 1), wherein the soluble TGF-β type II receptor has at least 85% amino acid sequence identity to SEQ ID NO:1 (100% identical) and wherein the amino acid sequence of the fusion protein is at least 85% identical to SEQ ID NO:2 (98.2% query match).
Romo et al. teach at [0017] a method of treating diseases associated to TGF-β dysregulation by administering to a mammal in need thereof the soluble isoform of the TGF-β receptor. Romo et al. teach that associated diseases include “any disorder related to dysregulation of TGF-β signals, such as fibrosis. Romo et al. also teach the treatment of hepatic fibrosis (see abstract) by providing the TGF-β II receptor fused to a ligand by means of a vector comprising the fusion protein (see also [0091]). Therefore, Romo et al. anticipates claims 1-4 and 7.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1 and 4-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Pat. Pub. 2019/0112352 (Romo et al.) in view of any one of Bartram et al. (The Role of Transforming Growth Factor β in Lung Development and Disease. CHEST 125: 754-765, 2004) or Lui et al. (cited by Applicant) or Dooley et al. (TGF-β in progression of liver disease. Cell Tissue Res. 347: 245-256, 2012).
The disclosure of Romo et al. is provided above. Romo et al. does not explicitly state that the mammal to be treated is a human. Romo et al. does not explicitly recite that the fibrosis is lung fibrosis or skin fibrosis and Romo et al. does not explicitly recite the disorders and diseases recited in claim 6.
Bartram et al. teach that TGF-β is implicated in pulmonary fibrosis and that idiopathic pulmonary fibrosis is associated with increased levels of TGF-β in humans (see page 757 and Table 1).
Liu et al. teach that primary biliary cholangitis is a progressive autoimmune liver disease in humans. Liu et al. teach that TGF-β enhances fibrogenesis in subjects with primary biliary cholangitis (see page 5835, last sentence) and contributes to the development of PBC.
Dooley et al. teach that TGF-β is a central regulator in chronic liver disease in humans and contributes to fibrosis in the liver (see page 245, first sentence). Dooley et al. teach that NASH is a chronic liver disease.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Romo et al. in human subjects with fibrosis of the liver or lung or skin and in subjects with non-alcoholic steatohepatitis (NASH) or idiopathic pulmonary fibrosis or primary biliary cholangitis (PBC) because the prior art of Bartram et al., Liu et al. and Dooley et al. all teach that TGF-β is a central regulator of fibrosis in humans and in various organs, including the liver, lung and skin. Additionally, Bartram et al., Liu et al. and Dooley et al. teach that NASH, idiopathic pulmonary fibrosis and PBC are all diseases/disorders of fibrosis in which TGF-β is implicated. One of ordinary skill in the art would be motivated to treat fibrosis in a human subject wherein the fibrosis is in the liver or lung or skin with the method of Romo et al. because inhibition of TGF-β with the fusion protein of Romo et al. would be expected to inhibit TGF-β and therefore reduce the fibrosis in the affected tissue. One would also be motivated to treat any one of the specific conditions of NASH, idiopathic pulmonary fibrosis and PBC because the prior art of Bartram et al., Liu et al. and Dooley et al. teach that TGF-β induced fibrosis is a contributor to the diseases. One would have a reasonable expectation of success in treating the stated tissues and conditions because Mono et al. teach that administration of a fusion protein of the soluble TGF-β receptor II protein with a stabilizing agent inhibits fibrosis.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Budi et al. TGF-β as a driver of fibrosis: physiological roles and therapeutic opportunities. J. Pathol. 254: 358-373, 2021.
Parola et al. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol. Aspects Med. 65: 37-55, 2019.
Zhao et al. Signal Transduction and Targeted Therapy. Targeting fibrosis: mechanisms and clinical trials. 7: 206, 2022 (21 pages).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine J Saoud whose telephone number is (571)272-0891. The examiner can normally be reached M-F, 8am-4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel E Kolker can be reached at 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Christine J Saoud/Primary Examiner, Art Unit 1645