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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/11/2025 has been entered.
Status of the application
Receipt of applicant’s remarks and claim amendments filed on 07/25/2025 are acknowledged.
In light of applicants’ filed declaration, previous 102(a)(a) rejection is withdrawn.
However, applicants arguments for previous 112(a) written rejection are found not persuasive, and accordingly, the previous rejection is maintained and modified to address claim amendments.
Applicants provided data in the filed response should be in the form of declaration, since these are supplemental data, not in the original disclosure and is interpreted as statements.
Claim Rejections - 35 USC § 112 – Written Description [Modified]
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 13-14, 16 and 25-28 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 claim(s) contains 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.
The rejection is based on the requirement(s), i.e., the guidelines provided by the MPEP 2163.04. These are listed below:
(A) identify the claim(s) limitations at issue, and
(B) establish a prima facie case by providing reasons why a person skilled in the art at the time the application was filed would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed. The MPEP 2163 further provided or expanded the guidelines for the written description requirements.
(A) IDENTIFY THE CLAIM LIMITATIONS AT ISSUE:-
In light of elected species, the claims are drawn to a method for maintaining liver homeostasis in a subject with liver fibrosis, the method comprising administering to a subject a pharmaceutical composition comprising an ECM1 protein represented by SEQ ID NO:3, wherein the pharmaceutical composition is administered orally, intramuscularly or intravenously.
The rejection is based on ‘what is known in the art’, ‘what is shown in the specification’, ‘what applicants are claiming’, and based on these facts, analysis concludes or showed evidence towards whether applicants have possession of claimed subject matter or not.
Disruption or imbalance in liver homeostasis results in liver diseases or inflammation of liver etc. These can be caused by external virus or food poisoning or toxins etc. However, the mechanism of each one is different and so the treatment or ‘maintaining liver homeostasis’ is expected to be different.
It seems that shown data in the specification simply say ECM1 protein, which can be interpreted as all ECM1 proteins from all species. ECM1 from different species have different protein lengths and can expect different properties. Applicants specification states that “the present invention relates to an ECM1 protein and a variant thereof. In a preferred embodiment of the present invention, the amino acid sequence of the ECM1 protein is as shown in SEQ ID NO: 1 or 3. The present invention also includes a polypeptide or protein with the same or similar function that has 50% or more (preferably 60% or more, 70% or more, 80% or more, more preferably 90% or more, more preferably 95% or more, most preferably 98% or more, such as 99%) homology with the sequence as shown in SEQ ID NO. 1 or 3 of the present invention. Among them, SEQ ID NO.: 1 is a murine ECM1 protein; SEQ ID NO.: 3 is a human ECM1 protein”.
So, did applicants show data for the elected species, viz., SEQ ID NO:3?
Further, claims recite orally, intramuscularly or intravenously for mode of administration. However, shown data is limited to injection through a tail vein, as shown in example 4.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a variability in the genus or broadly claimed subject matter, and if the variability expects unpredictability for the claimed subject matter, then specification must describe the genus with divergent species, so that a skilled person in the art can understands claimed invention and can reproduce applicants claimed invention. In this case, protein chemistry is probably one of the most unpredictable areas of biotechnology and consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. So, the absence of description with divergent species makes the invention unpredictable, and cannot be envisioned by a skilled person in the art.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "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. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure. See MPEP 2163 II(A)(3)(a)(ii).
The number of species that describe the genus must be adequate to describe the entire genus. However, if there is substantial variability, a large number of species must be described.
The question is that with several possible sequences for ECM1 protein, based on its definition in the specification, will all possible ECM1 protein be capable of retain its property? Do applicants provide enough description for nexus between elected species and shown data, so that a skilled person in the art understands the claimed invention?
(B) ESTABLISH A PRIMA FACIE CASE BY PROVIDING REASONS WHY A PERSON SKILLED IN THE ART AT THE TIME THE APPLICATION WAS FILED WOULD NOT HAVE RECOGNIZED THAT THE INVENTOR WAS IN POSSESSION OF THE INVENTION AS CLAIMED IN VIEW OF THE DISCLOSURE OF THE APPLICATION AS FILED:
The further analysis for adequate written description considers, see MPEP 2163, the following:
(A) Determine whether the application describes an actual reduction to practice of the claimed invention:
Description is very generic. Shown data is also generic, since it says ECM1 protein, which is defined in the specification very broadly. No data is shown for elected species or any specific species. No description is provided with respect to variability of ECM1 protein and their end or expected properties.
Only in Example 4, adeno-associated virus-medicated ECM1 expression inhibits CCl4 induced liver fibrosis. No nexus between shown data in Examples 1-3 and 4 are described.
Description of dosage amounts are very generic.
Accordingly, applicants failed to describe actual reduction to practice of the claimed invention.
(B) If the application does not describe an actual reduction to practice, determine whether the invention is complete as evidenced by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole:
Drawings show expression levels of ECM1 are low in liver fibrosis as evidenced from at least from knock out ECM1 shown data. Further, ECM1 protein inhibits the activation of TGF-beta1 and activation of HSC by interacting with integrin alpha V. Finally, adeno-associated virus-medicated ECM1 expression inhibits CCl4 induced liver fibrosis.
(C) If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics, such as structure/function correlations, as evidenced by other descriptions of the invention that are sufficiently detailed to show that applicant was in possession of the claimed invention:
With regard to ECM1 protein scope or definition, which can generate thousands of ECM1 variants and these are expected to show different properties, since protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Mode of administration is also critical in maintaining liver homeostasis or treating liver fibrosis related diseases. Claimed subject matter claiming all possible modes of administration. There is also unpredictability in the mode of administration, for example, Bruno et al [Ther Deliv, 2013 Nov, 4(11), 1443-1467] teach that the peptide and protein therapeutic market has developed significantly in the past decades, delivery has limited their use. Although oral delivery is preferred, most are currently delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract. Therefore, absorption enhancers, enzyme inhibitors, carrier systems and stability enhancers are being studied to facilitate oral peptide delivery. Additionally, transdermal peptide delivery avoids the issues of the gastrointestinal tract, but also faces absorption limitations. Due to proteases, opsonization and agglutination, free peptides are not systemically stable without modifications. This review discusses oral and transdermal peptide drug delivery, focusing on barriers and solutions to absorption and stability issues. Methods to increase systemic stability and site-specific delivery are also discussed. [See abstract and whole article].
It appears that known art reveals nexus between liver fibrosis and ECM1. For example, Zhao [Acta Pharmaceutica Sinica, 01 Oct 2014, 49(10); 1365-1371] describes liver fibrosis is a pathological process of the excessive accumulation of extracellular matrix [see abstract]. Jacobs [US2014/0273275A1] describes ECM1 levels are upregulated in the presence of liver fibrosis [see 0079]. So, the disclosures of Zhao and Jacobs are controversial to applicants claimed method.
In view of above a skilled person in the art can expect unpredictability in applicants claimed subject matter. There are no physical/chemical/structural features that applicants have tied to claimed subject matter, making it impossible for an individual of ordinary skill in the art to determine which of the genus of claimed conditions would be effective in making the claimed method. Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement.
Accordingly, it is deemed that the specification fails to provide adequate written description for the the claimed subject matter and does not reasonably convey to one skilled in the relevant art that the inventors had possession of the entire scope of the claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658