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 .
Status of the application
Receipt of applicant’s remarks and claim amendments filed on 04/05/2026 are acknowledged.
For clarification purpose, since applicants changed the elected species for the claimed method several times, in absence of explanation from applicants, the examiner chose “treating” as a species for the claimed method.
Applicants arguments and filed declaration for previous 112(a) written rejection are found not persuasive, and accordingly, the previous rejection is maintained. Also, since independent claim is limited to SEQ ID NO: 1 or 3, and administration is limited to subcutaneously, and so, the scope is changed. Accordingly, the previous written description rejection is modified.
In addition, a new Claim Objection is made.
Response to Arguments
Applicants’ main arguments are based on the filed declaration. However, post-filing declaration cannot be considered in this case, see the following reasoning:
In fact, such evidences cannot be used to cure an otherwise defective specification/disclosure, as evidenced from the board cases. See Appeal 2021-002851 (15/993,172) (“In short, Dr. Steinman’s declaration makes clear that the therapeutic data, which is not part of Appellant’s Specification, is part of the data that he considers necessary to provide reasonable predictability of treatment with a blocking antibody to CD49e to enable the claimed invention without undue experimentation … Notably, Dr. Block does not state that he has only reviewed the experimental work set forth in the Specification. See In re Wright, 999 F.2d 1557, 1563 (Fed. Cir. 1993) (noting that declaration evidence failed to support enablement because the declarants did not even indicate in their affidavits that they reviewed the Specification … While a post-filing declaration may be used to show the accuracy of a statement in the specification, it cannot ‘render an insufficient disclosure enabling.’ In re Brana, 51 F.3d 1560, 1567 n.19 (Fed. Cir. 1995).”). See also Appeal 2021-002851 (15/993,172) (“Paragraph 102 of the Specification just generally identifies a broad range of “effective dose of an anti-α5 agent of the invention [that can be] administered alone, or combined with additional active agents for the treatment of a condition as listed above.” There is nothing else in the Specification for one of ordinary skill in the art to determine what dose and agent would be able to treat ALS in humans in the manner required by the claims. As noted, Dr. Steinman’s Declaration refers to an experiment that may shed light on that, but that evidence is not part of the Specification, and it is not even clear that the experiment was carried out by the time of the effective filing date of the application. While a post-filing declaration may be used to show the accuracy of a statement in the specification, it cannot “render an insufficient disclosure enabling.” In re Brana, 51 F.3d 1560, 1567 n.19 (Fed. Cir. 1995).”).
So while a post-filing declaration can be used for some purposes (e.g., show what the state of the art was as of the effective filing date, verify statements in the specification as truthful, etc.), it cannot be used to replace the specification. Remember too that enablement must occur as of the filing date, not some later date. “Enablement, or utility, is determined as of the application filing date.” In re Brana, 51 F.3d 1560, 1567 n.19, 34 USPQ2d 1436, 1441 n.19 (Fed. Cir. 1995). See Appeal 2007-4458 (09/036,613) (“[A]lthough evidence obtained after the application’s filing can be used to verify the accuracy of statements already in the Specification, it cannot be used to supplement the Specification’s disclosure. See id.; see also In re Hogan, 559 F.2d 595, 605, (CCPA 1977) (‘[U]se of later publications as evidence of the state of art EXISTING on the filing date of an application” is acceptable.’”).
This suggests that Applicants did not provide an sufficient description so that a skilled person can understand or enabling disclosure as of the filing date. Later experiments proving these things (even if they existed) would not be enough. Again, the specification must describe and enable the invention, not some later experiments performed by the Applicants. See Appeal 2015-007406 (13/880,113) (“It is an applicant’s obligation to supply enabling disclosure without reliance on what others may publish after he has filed an application on what is supposed to be a completed invention. If he cannot supply enabling information, he is not yet in a position to file.” In re Glass, 492 F.2d 1228, 1232 (CCPA 1974).”). It sounds like maybe Applicants jumped the gun here and filed too quickly (assuming the invention works at all)?
With regard to cited Jacobs document, applicants argue that Jacobs merely mentions that ECM1 level were detected in liver fibrosis patients but does not provide comparative data with healthy individuals.
The shown data in Jacobs is from experimental evidence. Since liver fibrosis is unhealthy, that implies that the shown data is compared with healthy patients.
Claim Objections
Claim 15 is objected to because of the following informalities: in line 3, the “SEQ IN No.1” should be replaced with “SEQ ID NO:”. Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Written Description [Maintained and 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 “treating” as species for method, claims are structured as a method for treating liver fibrosis 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: 1 or 3, wherein the pharmaceutical composition is administered subcutaneously, intramuscularly or intravenously.
The rejection is based on ‘what applicants are claiming’, ‘what is shown/described in the specification’ and ‘what is known in the art’. Based on these facts, the following analysis explains whether applicants have possession of claimed subject matter or not.
Disruption or imbalance in liver homeostasis leads to 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.
Claims require administration of ECM1 protein pharmaceutical composition. However, the pharmaceutical composition is not defined, i.e. its complete structure, for subcutaneous administration and so, the ECM1 can be in any solvent, at any pH and composition can include other components in it. Dosage amounts are very broad, ranges from 0.0001 – 100 mg/kg body weight for the claimed ECM1. Subject can be human or non-human mammal.
However, shown data in the specification is limited (i) inhibition of activation of human HSC by ECM1 protein and (ii) injecting ECM1 gene to the subject. There is no step of administration of ECM1 protein pharmaceutical composition to the subject in the shown data.
In example 4, shown data is limited to injecting ECM1 gene, and there is no step of administration of ECM1 protein.
So, there is no shown data for claimed SEQ ID NOs: 1 or 3 or any related proteins for the claimed method. Described preparation of pharmaceutical composition is theoretical and no actual preparative methods or no example(s) are provided.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a variability in the 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, environmental conditions on the protein structure and function cannot be predicted. So, absence of description of pharmaceutical composition and/or protein administration 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 subject matter 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, in absence of administration of ECM1 protein pharmaceutical composition and its preparative methods, will all possible ECM1 protein pharmaceutical compositions, such as at all pH values and all possible solvents etc., be capable of retain its property? Do applicants provide enough description for nexus between claimed ECM1 protein administration 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:
Only Examples 3.3.3 and 4 are related to claimed method. There are no shown data to prepare composition of ECM1 protein, and no shown data for administration of ECM1 protein.
In example 3.3.3, the shown data describes inhibition of activation of human HSC by ECM1 protein. It appears that there is no step of administration of ECM1 protein composition.
In example 4, shown data is limited to injecting ECM1 gene, and there is no step of administration of ECM1 protein composition.
So, there is no shown data for claimed SEQ ID NOs: 1 or 3 or any related proteins for claimed method.
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. No ECM1 protein administration is demonstrated.
(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:
Formulations of proteins is one of the challenging task, because development of stable protein formulations may require even more resources and effort than conventional small molecule pharmaceuticals. Proteins typically have more stability issues as a result of their complexity and delicate structural stability. So, both the physical and chemical stability of biopharmaceuticals are critical and need to be optimized when formulating a protein, in order to optimize the outcome after processing and storage. See the following review articles on protein formulations.
Vaishya [Expert Opinion on Drug Delivery, 2015, 12(3), 415-440] describes delivery protein therapeutics, specifically states that (i) instability may arise at many stages including formulation development and during release, (ii) proteins are susceptible to aggregation and denaturation via exposure to organic solvents, oil–water interface and at high concentration in aqueous solution and (iii) protein may denature during release leading to incomplete release, hence influence of excipients and polymers on protein stability should be explored before the formulation development etc. [see abstract and Article highlights in page 416].
Jorgensen [Expert Opinion on Drug Delivery, 2009, 6(11), 1219-1230] describes several factors which contribute towards stabilizing peptides and proteins in pharmaceutical formulations and considerations in the choice of excipients [see whole document].
Wang [Protein Science, 2015, vol.24, 1031-1039] also describes limitations and uncertainties on developing protein formulations [see whole document].
So, based on above evidences, structural and functional properties of proteins are very sensitive to small changes in pH or solvent or excipient etc., in other words these changes drastically change the function of protein.
In addition to above, it appears that known art reveals nexus between liver fibrosis and ECM1. For example, Jacobs [US2014/0273275A1] describes ECM1 levels are upregulated in the presence of liver fibrosis [see 0079]. So, the disclosures of 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
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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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