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 .
Claims 1-3,5-9, 11-16, 31-34 and 36-37 remain pending and examined on the merits.
Applicant’s response (amendments, arguments, IDS) is acknowledged.
Any rejection no longer of record has been overcome by amendment/argument.
The examiner remains open to further interview.
Election/Restrictions-Withdrawn
Upon further consider the choice of C1 esterase inhibitor is open, including variants within a pool thereof (see e.g. relevant background sections within U.S. Patent Publication No: 20220265786).
Claim Rejections - 35 USC § 112(a)(i)/(pre-AIA ) – Written Description, New,
Necessitated by IDS
The following is a quotation 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.
Claims 1-3,5-9, 11-16, 31-34 and 36-37 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.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing/identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In this case, the claims are drawn to “improving long-term allograft survival” or “improving long-term allograft function” via a “therapeutically effective amount of [ANY] C1 esterase inhibitor”. The specification describes and guides that applicant was in possession of certain C1 esterase inhibitors capable of carrying out the intended, claimed invention. However, Feussner et al. (Biochemical comparison of four commercially available C1 esterase inhibitor concentrates for treatment of hereditary angioedema, Blood Components, Transfusion, 2014, Vol. 54, pages 2566-2573 – cited in the IDS of 8/10/26) relates that compositions comprising C1 esterase inhibitor concentrates can contaminating plasma proteins that may compromise function (see Discussion page 2570, para 3), and that no pharmacopoeia requirements exist for C1 esterases (page 2566, Background). Based on a lack of regulation and the potential impact of impurities on C1 esterase compositions, and whether or not all C1 esterases function as intendedly claimed here, based on the breadth of the class as claimed, there are issues raised under the possession prong of written description as to whether applicant was in possession of employing ‘any’ C1 esterase inhibitor and shown for “improving long-term allograft survival” or “improving long-term allograft function. Further evidence is required to show, beyond the specification as filed, that ANY C1 esterase and/or C1 esterase composition would have been guided to carry out the instantly claimed invention based on the representative examples within the instant specification.
This was further touched in previously at the restriction stage (see 1/30/25 restriction, page 1):
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See also the previous Interview relevant thereto:
Summary of Interview: Change of Election (Species) to a Pooled Mixture/Batch of Structures/Sequences of Human C1 Esterase Inhibitors rather than 'Any' Single, Distinct Structure/Sequence of Human C1 Esterase Inhibitor (Latter Original Species Election Found to be Drawn to Structurally/Sequentially Variable Species).
Original Species Election Structure/Sequence Uncertainty
The species election uncertainty as to the structure/sequence to be searched relevant to the originally elected "human C1 esterase inhibitor" was triggered by the initial non patent literature text-based search thereof yielding a State of the Art review article that the elected species human C1 esterase inhibitor contains highly variable amino acid sequences - yet no sequence listing was present in the instant application. A relevant passage of Karnaukhova* stated (as recited of record):
"One more characteristic feature of the N-terminal domain is the presence of a highly repetitive and variable region in its amino acid sequence with 14 tandem repeats of the tetrapeptide GlnPro-Thr-Thr [66]. Variations in amino acid sequence and a high content of intrinsically heterogeneous carbohydrate moiety significantly contribute to the heterogeneity of the whole protein. C1INH molecule contains four cysteine residues which are engaged in two disulfide bridges that connect the C- and N- domains and maintain the protein integrity [62]. There are no free thiol groups in the C1INH molecule."
Based on the initial non-patent literature search results of Karnaukhova it could not be determined 'what' the intended structure/sequence of the elected species human C1 human esterase inhibitor was to be searched/examined on the merits. Further, with no structures and/or sequence list of record and the uncertainty as to whether a sequence listing (computer readable form (CRF), statement, and fee) would need to be filed - a proper search of other structure/sequence databases such as CAS's STN and/or the USPTO internal ABSS sequence database of the elected species could not be reasonably carried out. Based on these findings in Kamaukhova and all considerations relevant to the structure/sequence uncertainty and search thereof in the relevant databases as to the elected species, the examiner felt it was best to seek clarification on the record as to the intended elected species structure/sequence to be searched/examined on the merits and to give applicant sufficient time to provide any further evidence thereto (e.g. a sequence listing; evidence as to structure/sequence; etc.). Hence, the processing of a supplemental restriction requirement was necessary to obtain such clarification and allow sufficient time for submission of further evidence (e.g. sequence listing; evidence as to structure/sequence; etc.) as to the intended species election structure/sequence for search/examination on the merits, so that a reasonable search of the intended species election could carried out in all relevant search databases.
Change of Species Election:
To a Pooled Mixture/Batch Rather Than Any Distinct Structure/Sequence Species
As a result of the interview, applicant's representative clarified that the structure/sequence is not critical/essential as of the original species election of human C1 esterase inhibitor of the claimed invention.
Therefore, applicant would be filing a response (received the following day after interview on 3/21/25) changing the species election to a batch/mixture of 'any' structure/sequence of human C1 esterase inhibitor, without such being critical/essential to the claimed invention. Express/inherent support for this new/change of species election to said mixture/batch is found in e.g. instant specification para [0032]:
[0032]
In various embodiments, C1-Inhibitor can be produced according to methods known to one of skill in the art. For example, plasma-derived C1-INH can be prepared by collecting blood plasma from several donors. Donors of plasma should be healthy as defined in the art. Preferably, the plasma of several (1000 or more) healthy donors is pooled and optionally further processed. An exemplary process for preparing C1-inhibitor for therapeutic purposes is disclosed in U.S. Pat. No. 4,915,945, the disclosure of which is hereby incorporated in its entirety. Alternatively, in some embodiments C1-INH can be collected and concentrated from natural tissue sources using techniques known in the art. Commercially available products comprising C1-inhibitor are, e.g. plasma-derived CINRYZE® (Viropharma), recombinant RUCONEST® or RHUCIN® (both Pharming), and plasma-derived BERINERT® (CSL Behring). BERINERT® is indicated for treatment of hereditary angioedema and congenital deficiencies. Recombinant C1-INH can be prepared by known methods.
*Prior Art Reference of Record: Karnaukhova. Review Article: C1-Inhibitor: Structure, Functional Diversity and Therapeutic Development. Current Medicinal Chemistry, 2022, (29): 467-488); see e.g. page 469, left column.
Other Relevant Passages of the Instant Specification Discussed During Interview Include the Following:
[0029]
The terms “C1-Inhibitor,” “C1 esterase Inhibitor,” “C1-INH” and “C1INH” refer to a serine protease inhibitor that inhibits proteases associated with the complement, contact, fibrinolytic and/or coagulation systems, such as proteases C1r and C1s in the classical pathway as well as MASP-1 and MASP-2 in the MBL complement pathway, or associated with the kallikrein-kinin system, such as plasma kallikrein and factor XIIa, and or associated with the coagulation system, such as factor XIa. In addition, C1-INH can serve as an anti-inflammatory molecule that reduces the selectins-mediated leukocyte adhesion to endothelial cells. C1-INH as used herein can be a native serine protease inhibitor, as a protein or active fragment thereof, or it can comprise a recombinant peptide, a synthetic peptide, peptide mimetic, or peptide fragment that provides similar functional properties—e.g., the inhibition of proteases C1r and C1s, and/or MASP-1 and MASP-2 and/or factor XIIa and/or factor XIa. For further disclosure regarding the structure and function of C1-Inhibitor, see U.S. Pat. Nos. 4,915,945; 5,939,389; 6,248,365; 7,053,176; and WO 2007/073186, also U.S. Pat. No. 10,532,087; the content of all of which is hereby incorporated by reference.
[0030]
In some embodiments, the inhibitor is a plasma-derived or a recombinant C1-Inhibitor. In a further preferred embodiment said inhibitor is identical with the naturally occurring human protein or a variant thereof. The C1-INH shall encompass all natural occurring alleles which have the same function as the C1-inhibitor. In one embodiment said inhibitor is the human C1 Esterase Inhibitor.
[0031]
In another embodiment the C1-inhibitor according to the present invention is modified to improve bioavailability and/or half-life, to improve efficacy and/or to reduce potential side effects. The modification can be realized by recombinant or other steps. Examples for such a modification could be a glycosylation or an albumin fusion of the described C1-inhibitor. For further disclosure regarding the glycosylation and the albumin fusion of proteins see WO 01/79271, also U.S. Pat. No. 6,905,688, which is hereby incorporated by reference.
As such, the specification does not provide adequate written description of the claimed genus, that ANY C1 esterase inhibitor, based on the breadth of that genus and structural variability thereof and with compositions comprising such and lack of regulation thereof (see Feussner), and the limited representative examples thereof, was in possession of applicant at the time of filing, without further evidence. Without such, applicant may consider amendment to those C1 esterase inhibitors supported with the specification as filed.
Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Conclusion
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 8/10/26 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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 MAURY AUDET whose telephone number is (571)272-0960. The examiner can normally be reached on M-Th. 7AM-5:30PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/MAURY A AUDET/Primary Examiner, Art Unit 1654
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