DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/23/2026 has been entered.
Applicant’s arguments and amendments to the claims filed on December 23 have been received and entered. Claims 1, 5, 7, 9, 11, 13-14, 27-28 have been amended, while claims 2-4, 6, 8, 10, 12, 15-26 have been canceled. Claims 27-35 are newly added. Claims 1, 5, 7, 9, 11, 13, 14, 27- 35 are pending in the instant application.
Priority
This application is a Divisional of US application no 16/165,018 filed on 10/19/2018, which claims priority from foreign application EP 17198800.9 filed on 10/27/2017.
Claims 1, 5, 7, 9, 11, 13, 14, 27- 35 are under consideration.
New-Claim Rejections - 35 USC § 112 -necessitated by amendments
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, 5, 7, 9, 11, 13, 14, 27-34 and 35 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims are directed to an isolated long immunoglobulin diversity (DH) cassette (LDH cassette) comprising a recombinant DH construct comprising 5-60 different human DH gene segments wherein at least two DH gene segments are directly fused and encode at least 10 amino acids of a heavy chain CDR3 (HCDR3) amino acid sequence, wherein one fused DH gene segment comprises a human DH gene segment that is mutated to remove stop codons in reading frames (RF) 1, 2 and 3, wherein the other fused DH gene segment comprises a human DH gene segment flanked by a mouse intergenic region
Claims 14 and 35 are directed to an isolated immunoglobulin heavy chain locus comprising the isolated LDH cassette comprising a recombinant DH construct comprising 5-60 different human DH gene segments wherein at least two DH gene segments are directly fused and encode at least 10 amino acids of a heavy chain CDR3 (HCDR3) amino acid sequence, wherein one fused DH gene segment comprises a human DH gene segment that is mutated to remove stop codons in reading frames (RF) 1, 2 and 3, wherein the other fused DH gene segment comprises a human DH gene segment flanked by a mouse intergenic region., which is functional to express said HCDR3 amino acid sequence. Claims 35 recite an isolated immunoglobulin heavy chain locus comprises the same LDH cassette as above, wherein at least two germline DH gene segments are directly fused and encode at least 10 amino acids of a heavy chain CDR3 (HCDR3) amino acid sequence.
The genus comprises an isolated immunoglobulin heavy chain locus derived from any species of mammal that comprises a DH construct anywhere within the locus in presence and/or absence of endogenous immunoglobulin heavy chain locus that is functional to express said HCDR3 amino acid sequence.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that ''applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The genus comprises an isolated immunoglobulin heavy chain locus derived from any species of mammal that comprises a DH construct anywhere within the locus comprises "a long DH (LDH) cassette that includes 5-60 different human DH gene segments wherein at least two DH gene segments are directly fused and encode at least 10 amino acids of a heavy chain CDR3 (HCDR3) amino acid sequence. The recited cassette need only include different human DH gene encoding at least 10or 20 amino acids of a HCDR3. The specification as well as art teaches in order to generate a sequence that encodes a HCDR3 as specified in the claims, rearrangement must occur between: (i) VH gene segments, (ii) DH gene segments and (iii) JH gene segments. The specification teaches "after productive VDJ rearrangement is functionally expressed within a HCDR3 sequence" (see para. 333, fig. 3 and also Rosner et al Immunology 103:179-187, 2001, page 181-182). In the instant case, neither prior art nor instant specification provide any guidance to support an isolated immunoglobulin heavy chain locus derived from any species of mammal comprising the isolated LDH cassette as claimed that is inserted anywhere or replaces ang region of the endogenous locus, that would be functional to express said HCDR3 amino acid sequence as required by the claims.
The specification teaches mouse having heavy chain immunoglobulin loci comprising four different DH gene segment types (example 1, fig. 2and page 61-62 of the specification):
Bovine long IGHDS2 and DH 3.1 gene segments. Bovine antibodies with ultralong HCDR3s (50 - 61 aa) use IGHDS2. In this case, the IGHDS2 has been modified to encode TTVHQ (SEQ ID NO:5) amino acids at the 5' end. The bovine DH 3.1 gene segment has also been mutated to remove stop codons.
Artificial fusion germline DH gene segments (5 - 60 gene segments created by in silico joining of native human DH gene segments. In addition to being artificially fused, all stop codons in RF 1, 2 and 3 have been eliminated to increase the potential diversity of DH gene segments.
Synthetic DH gene segments (SynDH, FIG. 3) corresponding to the core N1-DHN2 portion of the HCDR3 region of LHCDR3 Abs extracted from IMGT and NCBI sequence databases.
Modified human germline DH gene segments D2-2, D2-15 and D3-16 that are longer than the average DH and have been shown (Briney, et al., PLoS ONE, e36750, 2012) to be used by normal human B cells to produce LHCDR3 Abs. All stop codons in RF 1, 2 and 3 have been eliminated in these DH segments to increase the potential diversity of the resultant LHCDR3 antibody repertoire
In the instant case, the specification lacks genus of artificial fusion DH gene segments containing 5 - 60 gene segments created by in silico joining of native human DH gene segments that have also been mutated to remove any stop codons in RF 1, 2, and 3 of the respective native DH gene segments encode the required at least 10 or 20 amino acid of CDRH3 other than human germline DH gene sequences that have been in silico fused so as to encode long HCDR3 regions as set forth in table 2 of the instant specification lack a written description. Further, while the claims recite a fusion of DH gene segments, but the specification as discussed above also requires the fused DH gene segments to "artificial," "germline," joined "in silico. The specification fails to describe what sequence of artificial fusion germline DH gene segments 5 - 60 gene segments created by in silico joining of native human germline DH gene segments that have also been mutated to remove any stop codons in RF 1, 2, and 3 fall into this genus other than those set forth in table 2. Further, the specification explicitly states’ at least two DH gene segments are directly fused DH gene segments, or separate gene segments, connected by an intergenic region. It is further disclosed that at least two human DH gene segments are directly fused, and in particular flanked by an RSS on both ends (see page 7, lines 17-20). In the instant case, none of the claims require the presence of an intergenic region connecting the two DH gene segments, nor that the gene segments are human germline DH gene segments flanked by an RSS on both ends. The claims as written requires a direct fusion of any human DH segment to another human DH gene segment, which is not disclosed in the specification as broadly claimed.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements or motifs which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998).
The skilled artisan cannot envision the detailed structure of the encompassed artificial fusion germline DH gene segments (5 - 60 gene segments created by in silico joining of native human DH gene segments that have also been mutated to remove any stop codons in RF 1, 2, and 3 of the respective native DH gene segments encode the required at least 10 or 20 amino acids of CDRH3 other than human DH gene sequences set forth in table 2 and any direct fusion of at least two human DH gene segments other than DH connected by an intergenic region and flanked by an RSS on both ends, and therefore 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the genus as embraced by the claims.
New-Claim Rejections - 35 USC § 112 -necessitated by amendments
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.
Claims 1, 5, 7, 9, 11, 13, 14, 27- 35 are rejected under 35 U.S.C. 112, 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(s), at the time the application was filed, had possession of the claimed invention. In the instant case, the recitation of limitation “..an isolated long immunoglobulin diversity (DH) cassette (claim 1) and isolated immunoglobulin heavy chain locus (claim 14) are considered new matter. Applicants point to page 34 and 56 (last two paragraph) of the specification for the specific support of the claimed amendment. However, upon further review of the instant specification, examiner could only find support for an isolated nucleic acid (intended for heavy chain variable gene segment). There is no explicit or implicit support for an isolated long immunoglobulin diversity (DH) cassette or an isolated immunoglobulin heavy chain locus as required by the claim. In fact, the specification at best directly support that the claimed construct and locus are manmade synthetic construct but lack support for the term isolated construct or an isolated immunoglobulin heavy chain locus. Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of an isolated long immunoglobulin diversity (DH) cassette and isolated immunoglobulin heavy chain locus, as claimed.
In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for an isolated long immunoglobulin diversity (DH) cassette (claim 1) and isolated immunoglobulin heavy chain locus as recited in claims of the instant application.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981) This is a new matter rejection.
Withdrawn- Claim Rejections - 35 USC § 103
Claims 1, 5, 9, 11, 13-14, 27-28, 30, were rejected under 35 U.S.C. 103 as being unpatentable over Tuaillon et al (Eur J lmmunol (2000) 30:2998-3005, IDS) as evidenced by Zemlin et al (J Mol Biol (2003) 334:733-749, IDS) and Stamatopoulos et al (Leukemia (1999) 13, 601–604), Wabl et al (US patent publication 20130219535, 8/22/2013) as evidenced by Briney et al (Immunology (2012) 137:56-64, IDS). Applicant’s argument and amendments to the claims obviates the basis of the rejection. Therefore, previous rejection of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Claims 1, 7 , 28 and 31 were rejected under 35 U.S.C. 103 as being unpatentable over Tuaillon et al (Eur J lmmunol (2000) 30:2998-3005, IDS) as evidenced by Zemlin et al (J Mol Biol (2003) 334:733-749, IDS) and Stamatopoulos et al (Leukemia (1999) 13, 601–604), Wabl et al (US patent publication 20130219535, 8/22/2013) as evidenced by Briney et al (Immunology (2012) 137:56-64, IDS) as applied above and further in view of Wang et al (USP 9644021, dated 05/09/2017, filed on 01/10/2014) and Wang et al (Cell, 2013, 153, 1379-1393). The rejection is withdrawn for the reasons discussed above.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Bradley et al (WO 2011/158009) teaches antibodies produced by humans and mice comprise HCDR3s that are at least 10 amino acids (see fig. 37).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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