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 .
Application Status
This action is written in response to applicant’s correspondence received on 10/16/2024. Claims 34, 38, 40-43, 46-48, 51-55 are currently pending.
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.
Priority
This application is a DIV of 16/481,001 filed on 07/25/2019 issued as PAT 11958891 on 04/16/2024; 16/481,001 is a 371 of PCT/US2018/015595 filed on 01/26/2018, which has PRO 62/487,135 filed on 04/19/2017 and PRO 62/450,804 filed on 01/26/2017.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 33 and 89. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Lipofectamine, Invitrogen, Thermo Fisher Scientific, GE Healthcare, Expi293F, which is a trade names or marks 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 Rejections - 35 USC § 112
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.
Claims 34, 38, 40-43, 46-48, 51-55 are 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.
Regarding claim 34, the claim recites the limitation “wherein the Wnt signal enhancing molecule comprises two polypeptides of SEQ ID NO: 82 and two polypeptides of SEQ ID NO: 50”. The specification teaches one embodiment of the claimed limitations (Example 10; Page 84, ¶[00233], last 6 lines) and shows a graphic schematic of the embodiment in FIG. 14A (middle scheme).
This language is considered to be indefinite because SEQ ID NOs: 50 and 82 set forth amino acid sequences of anti-TFR1 (transferrin receptor 1) fused with a Rspo2 (Fl 05R/Fl 09A) variant on each light chain (¶[00233], page 84, lines 9-13; Page 70, Table 1). Hence, the claimed Wnt signal enhancing molecule comprises two binding domains:
a) a first domain that specifically binds one or more transmembrane E3 ubiquitin ligases selected from Zinc and Ring Finger 3 (ZNRF3) and Ring Finger Protein 43 (RNF43), which is the Rspo2 (Fl 05R/Fl 09A) variant comprised in the polypeptide sequence set forth in part of SEQ ID NO: 50 (C-terminal; ¶[00233], page 84, lines 9-13); and
b) a second domain that specifically binds a tissue-specific cell surface molecule, wherein the Wnt signal enhancing molecule comprises two polypeptides of SEQ ID NO: 82 and two polypeptides of SEQ ID NO: 50, which is an anti-TFR1 IgG2 immunoglobin formed by two anti-TFR1 IgG2 heavy chains, set forth in SEQ ID NO: 82, and two anti-TFR1 IgG2 light chains, the sequence of which is set forth in part of SEQ ID NO: 50 (FIG. 14A, middle scheme).
However, TFR1 is ubiquitously expressed in all tissue types, as evidenced by Human Protein Atlas (Portal establishment methodology is taught by Uhlén, 2015, Science. 2015 Jan 23;347(6220):1260419; TFR1 (TFRC), ZNRF3, and RNF43 tissue expression data is retrieved in 2026; The pdf is attached and listed in PTO-892). The instant specification further teaches that “human transferrin receptor 1 (TFR1) … is broadly expressed in almost all types of cells” (Example 3, ¶[00223], lines 4-6). This limitation is mutually exclusive with the requirement of b) as claimed. Persons having ordinary skill in the art (PHOSITAs) would not be clear about the metes and bounds of the requirements.
In addition, the recitation “the tissue comprising…” is considered indefinite, because there is insufficient antecedent basis for this limitation in the claim. There are recitations for “a target tissue”, “tissue-specific Wnt”, and “tissue-specific cell surface molecule”, it is not clear whether a “tissue comprising the tissue-specific cell surface molecule” is the same tissue in any of these prior recitations because there is no requirement in the claim to have the “tissue-specific cell surface molecule” for the target tissue.
Regarding claim 40, it suffers from the same indefiniteness in claim 34 as discussed above. In addition, the recitation “the disease or disorder” is considered indefinite, because there is insufficient antecedent basis in the claim. The recited “condition” and “disorder” are not the same limitation.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 Written Description
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 40-43, 46-48, 51-55 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The independent claim 40 directs to an extremely broad genus of diseases wherein the claimed product genus relies on a functional limitation “wherein the disease or disorder is associated with reduced Wnt signaling or would benefit from increased Wnt signaling, …”, yet no common structure that underlie the recited functional limitation is disclosed. In another word, it claims what the therapeutic target does instead of what the therapeutic target is.
The specification recites numerous diseases (Pages 8-9, ¶[0029]; Pages 61-66, ¶[00188]-¶[00201]). However, the statements regarding how these diseases are associated with reduced Wnt signaling or whether these diseases would benefit from increased Wnt signaling are prophetic with no specific structural basis. With no representative disease model in vitro (cells) or in vivo (animals), the specification does not provide sufficient representation of the full scope of the genus as claimed.
Regarding the state of the art, the claimed invention emulates the function of Wnt signaling positive modulators R-spondins (RSPOs), serving as mimetics (Instant drawings, FIGs. 1-3). De Lau (Genes Dev. 2014 Feb 15;28(4):305-16) teaches that RSPOs primarily enhance Wnt signaling by promoting the degradation of the E3 ligases ZNRF3 and RNF43, serving as “anti-antagonists” by stabilizing the receptors for Wnt agonists (Page 305, Abstract; Page 312, Figure 5).
Regarding the state of the art, a review article by Clevers (Cell. 2012 Jun 8;149(6):1192-205) published before the effective filing date of the instant application teaches diverse mechanisms involved in Wnt signal dysregulation in diseases involving a wide range of tissue types, yet numerous questions remain and the mechanisms of Wnt signaling in diseases were still poorly understood (Page 1199, last section: Ten Outstanding Questions in the Wnt Field). By 2025, review articles by Xue (2025) confirms that, at the current state of art, RSPO-mediated activity results in the accumulation of Wnt receptors on the cell surface, leading to elevated β-catenin-mediated transcription (Page 10, left column, 1st ¶, last 3 lines; Page 12, Figure 5). However, Xue teaches that diverse mechanisms lead to reduced Wnt signaling (Page 12, Table 3), and numerous diseases with reduced Wnt signaling do not involve the canonical Wnt/β-catenin pathway, which may render RSPO-dependent mimetics ineffective in increasing Wnt signaling because the Wnt canonical receptors Fizzled and LRP5/6 are not involved (Page 12, Figure 5). The lack of definitive evidence for causal relationship between Wnt signal reduction and these diseases and the variant mechanisms underlying the observations (Page 12, Table 3) render it highly unpredictable whether increasing Wnt signal would be beneficial.
The disclosure of insufficient species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claim 40 is overly broad with insufficient evidence of possession at the time of filing to one skilled in the art. Thus, claim 40 does not meet the written description requirement, and the specification demonstrates a clear lack of possession of the full genus as claimed.
Claims 41-43, 46-48, 51-55 are also rejected for depending from the rejected claim 40 and failing to remedy the lack of written description therein.
Claim Rejections - 35 USC § 112 Enablement
Claims 40-43, 46-48, 51-55 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim 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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
The claimed invention directs to a method for treating or preventing a disease or condition in a subject in need thereof, wherein the disease or condition is associated with reduced Wnt signaling or would benefit from increased Wnt signaling. Thus, the methods require a reliable implementation of:
i) increase Wnt signaling in any subject in need thereof with a disease or condition associated with reduced Wnt signaling or would benefit from increased Wnt signaling;
ii) providing the subject in need thereof an effective amount of a pharmaceutical composition comprising a nucleic acid sequence encoding a tissue-specific Wnt signal enhancing molecule, which comprises a bispecific polypeptide with two specific binding domains, one domain specifically binding one or more transmembrane E3 ubiquitin ligases, and another domain specifically binding a tissue-specific cell surface molecule.
The Breadth of the Claims
The scope of the independent claim 40 limits the method for treating or preventing a broad genus of disease or condition defined by a functional limitation of being associated with reduced Wnt signaling or would benefit from increased Wnt signaling. Based on the broadest reasonable interpretation, these diseases or conditions could comprise any condition with any association with reduced Wnt signaling or any benefit resulting from increased Wnt signaling in any tissue. The specification further lists a none-limiting group of embodiments of diseases or conditions without describing or demonstrating how these conditions are associated with reduced Wnt signaling or how would any of these embodiments benefit from increased Wnt signaling. The scope of independent claim 40 encompasses distinct types of diseases (Pages 8-9, ¶[0029]; Pages 61-66, ¶[00188]-¶[00201]).
Guidance of the Specification
The specification is silent as to what adjustments are necessary to optimize the claimed method of preventing or treating any of the recited target diseases in the claims or the specification. No working example was offered to support the breadth of the claims to demonstrate how the RSPO mimetic-based strategy could activate or enhance Wnt signaling using a disease relevant tissue or in vivo animal model. Wnt signaling activity was measured using two cell lines containing a luciferase gene controlled by a Wnt-responsive promoter (Super Top Flash reporter assay, STF; Page 76, ¶[00216]). None of the cell models used for examples showed known mutations associated with Wnt signaling dysregulation. Therefore, the examples do not represent the full scope of the genus of diseased tissue types with variant Wnt dysregulation causes.
In the only in vivo example described in Specification on page 90, Example 15, the experimental Wnt signal enhancing molecule does not comprise the requisite two polypeptides of SEQ ID NO: 82 and two polypeptides of SEQ ID NO: 50. Rather, unrelated polypeptide or polynucleotide sequences are recited (Page 90, ¶[00246], last 6 lines). As a result, the specification is silent on how the claimed Wnt signal enhancing molecule, set forth in SEQ ID NOs: 82 and 50, could achieve Wnt signal enhancement in any disease model in vivo.
To a PHOSITA, the example in the instant application is not seen as working examples of treating any disease or condition associated with reduced Wnt signal using a Wnt signal enhancing molecule that requires the polypeptide sequences set forth in SEQ ID NOs: 82 and 50. Since SEQ ID NOs. 82 and 50 encodes anti-TFR1 light chain fused to a Rspo2 variant (F105R/F109A) and anti-TFR1 heavy chain, respectively (Page 84, ¶[00233], last 6 lines), the specification is silent as to how to achieve tissue-specific Wnt signal enhancement in vivo using a molecule with no tissue-specific binding domain because TFR1 and the binding target molecules of Rspo2, ZNRF3 and RNF43 do not show tissue-specific expression across tissue types, based on Human Protein Atlas (Portal establishment methodology is taught by Uhlén, 2015, Science. 2015 Jan 23;347(6220):1260419; TFR1 (TFRC), ZNRF3, and RNF43 tissue expression data is retrieved in 2026; The pdf is attached and listed in PTO-892).
The State of the Prior Art
Regarding the state of the art, a review article by Clevers (Cell. 2012 Jun 8;149(6):1192-205) published before the effective filing date of the instant application teaches diverse mechanisms involved in Wnt signal dysregulation in diseases involving a wide range of tissue types, yet numerous questions remain and the mechanisms of Wnt signaling in diseases were still poorly understood (Page 1199, last section: Ten Outstanding Questions in the Wnt Field). By 2025, review articles by Xue (2025) confirms that, at the current state of art, RSPO-mediated activity results in the accumulation of Wnt receptors on the cell surface, leading to elevated β-catenin-mediated transcription (Page 10, left column, 1st ¶, last 3 lines; Page 12, Figure 5). However, Xue teaches that diverse mechanisms lead to reduced Wnt signaling (Page 12, Table 3), and numerous diseases with reduced Wnt signaling do not involve the canonical Wnt/β-catenin pathway, which may render RSPO-dependent mimetics ineffective in increasing Wnt signaling because the Wnt canonical receptors Fizzled and LRP5/6 are not involved (Page 12, Figure 5).
Furthermore, some diseases that are associated with reduced Wnt signaling may not benefit from R-spondin (RSPO) mimetics, because the reduced Wnt signal is caused by mutations in the receptors. For example, certain types of osteoporosis are caused by a loss-of-function mutation in the Wnt receptors LRP5 (LRP5 mut), taught by Semenov (J Biol Chem. 2006 Dec 15;281(50):38276-84). Massink (Am J Hum Genet. 2015 Oct 1;97(4):621-6) teaches that loss-of-function mutations in the Wnt co-receptor LRP6 (LRP6mut) cause autosomal-dominant oligodontia, another disease associated with abrogated, i.e. reduced, Wnt signaling (Page 621, Abstract, line 11). These diseases would not have restored Wnt signals by enriching LRP5mut or LRP6mut expression using RSPO mimetics because LRP5mut or LRP6mut do not have normal Wnt receptor functions. These are evidence for a high degree of unpredictability of the claimed invention in restoring Wnt signaling.
The Level of Predictability in the Art
There is very high level of unpredictability in the art. The state of art with up-to-date summary of the current understanding indicates that the roles of Wnt signaling in disease etiology remain poorly understood. It is known in the art that heterogeneous mechanisms contribute to the correlative observations of Wnt signals. The existence of diseases associated with reduced Wnt signaling but unlikely to benefit from RSPO mimetics due to mechanistic incompatibility, e.g. those with LRP5mut or LRP6mut expression, further raises the unpredictability of the claimed invention. Since there is no disease relevant work example provided, not even cell models, prior art does not establish predictability.
The Quantity of Experimentation necessarily Needed
Considering the high level of unpredictability in the art, and the limited amount of direction provided by the specification, the quantity of experimentation necessarily needed to use the invention as claimed, especially with respect to treating diverse clinical types of diseases or conditions associated with reduced Wnt signaling or would benefit from increased Wnt signaling with no involvement of functional canonical Wnt receptors, is considerably high. For example, it would be necessary for one skilled in the art to identify optimal dosing, timing, and delivery routes for targeting specific tissue, and determine how to use a RSPO mimetic with no tissue targeting domain to achieve tissue-specific Wnt signal enhancement and use the invention to treat diverse clinical indications of Wnt signaling deficiency. Undue experimentation is required.
Conclusion of 35 U.S.C. 112(a) Enablement Analysis
After applying the Wands factors and analysis to claim 40, taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claim 40 is rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Claims 41-43, 46-48, 51-55 are also rejected for depending from claim 40 and failing to remedy the lack of enablement therein.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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