DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 21-40 are pending as amended 6/12/23, and are considered herein.
Claim Objections
Applicant is advised that should claim 26 be found allowable, claim 28 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 26 is drawn to a knockout pig, with decreased likelihood of antibody-mediated rejection. Claim 28 depends from Claim 26, but places limitation on the human recipient having antibodies to the epitopes, prior to the transplant. Such does not alter the structure of the composition claimed. Thus, despite a slight difference in wording, these claims have substantially the same scope.
Claim Rejections - 35 USC § 112
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 1-40 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 26-40 are generic for KO pigs, where alpha-1,3-galactosyltransferase and CMAH are expressed, but at a lower level, leading to a lower level of Neu5Gc epitopes and alphaGal epitopes, compared to a wild-type pig. Such is emphasized by the language in Claim 21, and the further limiting scope of 22, which again indicates Claim 21 is meant to include a scope more than a what is thought of as a double knockout. The other claims are also including such scope, as they separately depend from Claim 1. Separately depending claim 23 also indicates that broad claims include a lowered amount of epitopes, as well as completely absent, even when the KO pig has the enzymes in functional form, but at lower amounts. Claim 25 indicates that the epitopes lacking may just be on the glycoproteins of the cell surface. Claims 26-27 indicate likelihood of ADCC and hyperacute rejection is reduced when transplanted, but the epitopes may be present, just at a lowered amount. Claims 33-35 teach specific forms of mutation for the alpha-1,3-galactosyltransferase and CMAH, which produce the disruption.
It is the examiner’s contention that lowered, but still present levels of the enzymes, as well as lowered, but present amounts of the epitopes are directly linked, and must be completely absent to produce the effects, and the functions are all present, not singly in any particular instance (e.g., proteins all have lowered epitopes on their glycosylations, and the effects on reduced ADCC and hyperacute rejection occur if these epitopes are present).
The Specification teaches that alpha-1,3-Galactosyltransferase and CMAH produce the alphaGal epitope and Neu5Gc, respectively, and are not found in humans (paragraph 8). It is also recognized that these enzymes have been proposed to be knocked out, to reduce transplant rejection (e.g., Id.). Additionally, each single mutant has been made (e.g., paragraph 11). However, the combination has not been made, and thus, it is not known if it would be better (e.g., paragraph 12). Thus, the disclosure is directed to the dual KO mutant pig (e.g., paragraph 14) and use of its organs in research for tissue transplant and inhibiting rejection (e.g., paragraph 59). With regard to reduced, but not absent, expression, literal antecedent basis is provided reduced expression of the enzymes and concommittant reduced display of the epitopes (e.g., paragraphs 15-16). However, no embodiments of mutants that produce lowered levels of epitopes and lowered activity of the enzymes are provided, nor is there teaching of examples of pigs/organs/tissues/cells that separately have any specific effect. The only embodiments are that all these effects are together, and only with the complete knockout, not the partial activity and partial display of epitopes.
Still further, the Art does not teach which mutations produce lowered activity of these enzymes, and lowered levels of the epitopes, only the complete loss of the enzymes, and complete absence of the epitopes (e.g., Breimer, et al. (2011) “Gal/non-Gal Antigens in Pig Tissues and Human non-Gal Antibodies in the GalT-KO Era”, Xenotransplantation, 18: 215-228, ABSTRACT (Cited by Applicant in IDS of 1/19/24, reference 8 in the NPL literature).
The Art fails to teach mutations that produce lowered, but still present activity of the enzymes and lowered but present epitopes. In addition, if the epitopes are present, they are necessarily made by the enzyme, and would induce the various aspects of rejection.
Therefore, beyond the double KO pig, the artisan would not have understood Applicant to have been in possession of the lowered activity/lowered level of epitopes, and differential levels for producing the effects, separately.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 9,888,674. Although the claims at issue are not identical, they are not patentably distinct from each other because
Claim 21: Claim 1 teaches a KO big, where disruptions of alpha-1,3-galactosyltransferase and CMAH occur, providing decreased functional enzymes. As far as the epitopes displayed due to the enzymes, they necessarily are reduced.
Claim 22: The distinction between the claims here is that the present claim requires the lack of any functional expression of the epitopes. However, the present claims are to knock-outs, and the specification provides for the absence of these epitopes to reduce chance of rejection, and thus, it is clear the same claims of the patent are meant to embrace the absence of these epitopes which is obtained by the lack of expression of these enzymes.
Claim 23: As in claim 22’s analysis above, the absence of the enzymes necessarily provides for the result of lack of these epitopes.
Claim 24: as above, the KO pig would necessarily produce the same proteins with lack of these epitopes.
Claim 25: as above, the KO pig would necessarily produce the same proteins with lack of these epitopes.
Claim 26-32: the various characteristics evolve from the lack of expression of the genes, and thus, the effects are presumed to be present.
Claims 33-35: many of the same mutation choices are present in Claim 1.
Claim 36-40: Claim 2 recites organs, tissues and cells obtained from the KO pig of Claim 1. The specification provides the same extensive list of organs and tissues as found in Claims 37-40. As such, the essential written description is the same, and thus, the patent’s claims specifically embrace these embodiments.
In light of the patent, the invention is obvious. The Artisan would make it, and expect success, as it is claimed and covered by the essential written description of the invention.
Claims 21-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,667,500. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 21: Claim 1 teaches a method requiring a knockout pig with disrupted alpha-1,3-galactosyltransferase and CMAH genes, producing less of these enzymes. Claim 5 teaches improving hyperacute rejection, using an organ with these same genes having reduced expression, and the specification provides, as essential written description, deriving the organ from the same pigs as Claim 1. Claim 6 teaches another method of producing a glycoprotein of interest, by using similar knockout pigs.
Claim 22: the specification teaches as essential written description, the knockout, which has these enzymes completely knocked out of these two enzymes.
Claim 23: in the embodments taught for complete knockout, there is necessarily no expression of these epitopes.
Claim 24: the pigs will necessarily produce these glycoproteins.
Claim 25: as above, the KO pig would necessarily produce the same proteins with lack of these epitopes.
Claim 26-32: the various characteristics evolve from the lack of expression of the genes, and thus, the effects are presumed to be present.
Claim 33-35: Claims 4 and 8 teach these mutations.
Claim 36-40: Claims 2-3 teach livers of the pigs, and Claim 5 teaches generic organs, tissues and cells, which is provided with essential written description for the whole of the tissues, organs and cells that is presently claimed (e.g., specification, paragraph 74).
In light of the patent, the invention is obvious. The Artisan would make it, and expect success, as it is claimed and covered by the essential written description of the invention.
Claims 21-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,666,039. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 21: Claim 1 teaches a liver or liver tissue, derived from a pig comprising disrupted alpha-1,3-galactosyltransferase and CMAH genes, which is provided for human subject. As such the pig must be present. Claims 10 and 17 similarly require such pig.
Claim 22: As essential written description for the pig, complete knockout is taught (e.g., specification, paragraph 11).
Claim 23: as a consequence, the KO pigs lack these epitopes, necessarily.
Claim 24: the pig necessarily produces these proteins, and hence it is part of the pig.
Claim 25: as above, the KO pig would necessarily produce the same proteins with lack of these epitopes.
Claim 26-32: the various characteristics evolve from the lack of expression of the genes, and thus, the effects are presumed to be present.
Claim 33-35: Claims 7-9, 14-16, and 19-21 teaches these same mutations.
Claim 36-40: Claims 1 teaches pig liver, and Claim 10 teaches organs, tissues and cells, and Claim 17 teaches cells. Additionally, the specification provides essential written description for these organs, tissues and cells (e.g., paragraphs 48-51).
In light of the patent, the invention is obvious. The Artisan would make it, and expect success, as it is claimed and covered by the essential written description of the invention.
Response to Argument
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT M KELLY whose telephone number is (571)272-0729. The examiner can normally be reached M-F: 8a-5p.
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ROBERT M. KELLY
Examiner
Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638