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 .
DETAILED ACTION
Claims 1, 2, 4-6, 10, 14, 16, 19, 20, 22, 23, 27, 29, 31, 33, 35, 36, 38, 39, 41, 44, 46, 50 and 52-54 are currently pending.
Election/Restrictions
Applicant’s election without traverse of the invention of Group I, claims 1, 2, 4-6, 10, 14, 16, 19, 20, 38, 39, 41, 44, 46, 50, 52 and 53, in the reply filed on 15 Oct. 2025 is acknowledged.
Claims 22, 23, 27, 29, 31, 33, 35, 36 and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 15 Oct. 2025.
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.
Claims 1, 2, 4-6, 14, 16, 19, 20, 38, 39, 41, 46, 50, 52 and 53 are rejected under 35 U.S.C. 112(a) 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 1, 2, 4-6, 14, 16, 19, 20, 38, 39, 41, 46, 50, 52 and 53 recite a recombinant microorganism comprising nucleic acid sequences that encode a therapeutic protein, a secretion sequence and a pro-peptide, wherein the pro-peptide can be any sequence. As evidenced by Le Loir et al., Journal of Bacteriology 180.7 (1998): 1895-1903, the genus of pro-peptides encompasses a diverse range of peptides up to 200 residues in length that are found in association with secreted bacterial enzymes and have uncertain roles in secretion, folding, and/or stability of the mature protein (p. 1895, 2nd ¶).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species sufficient to show the applicant was in possession of the claimed genus (MPEP 2163). A "representative number of species" means that the species which are adequately described are representative of the entire genus (Id.). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus (Id.).
The instant specification describes only a single species of pro-peptide, namely LEISSTCDA; SEQ ID 123 (Published Spec. US20240092869, [0019]; [0027]; Table 8). The specification does not provide any additional species of pro-peptides capable of promoting expression and/or secretion of a LEKTI domain protein in the context of the claimed recombinant microorganisms and also fails to provide any teachings or guidance (e.g., a structure-function relationship or other guidance as to what types of pro-peptides would be suitable for use in the claimed invention) that would allow one of ordinary skill in the art to identify other members of the genus. Thus, the specification as filed does not evidence possession of the full scope of the claimed genus of pro-peptides (see also, MPEP 2163, II. 3. - a patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 4-6, 10, 14, 16, 19, 20, 38, 41, 44, 46, 50, 52 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of US20190040116 to Whitfill et al. in view of WO2020206221 to Azitra, as evidenced by US20240166990 (in the case of claims 6 and 44) and Le Loir et al., Journal of Bacteriology 180.7 (1998): 1895-1903 (in the case of claims 10 and 41).
Regarding claims 1, 16, 19, 20, 38 and 46, Whitfill teaches therapeutic compositions for treating a skin disorder comprising a recombinant microorganism capable of secreting a therapeutic polypeptide which is a LEKTI domain protein, wherein the organism comprising (i) a first coding sequence comprising a nucleic acid sequence encoding the therapeutic polypeptide; and (ii) a second coding sequence comprising a nucleic acid sequence encoding one or more secretion sequences that are not associated with the therapeutic polypeptide in nature, wherein the first and second coding sequences are in-frame (i.e. operably linked) ([0006]-[0020]; [0045]-[0063]; Examples). The LEKTI protein can be encoded by SPINK5 and can include one or more of LEKTI domains D1-D15, and the composition can be used to treat Netherton Syndrome (NS), which is caused by a defect in SPINK5 ([0006]-[0011]; [0051]-[0054]).
Regarding claims 6 and 38, Whitfill teaches the first and second coding sequences can be operably linked to a promoter ([0068]).
Regarding claims 14 and 50, Whitfill teaches the microorganism can be Staphylococcus, Streptococcus, Corynebacterium spp., including particularly Staphylococcus epidermidis ([0045]-[0046]).
Regarding claim 52, Whitfill teaches that the composition can comprise a carrier and can be in any form suitable for application to the body surface, such as a cream, lotion, solution, gel, ointment, emulsion, or the like ([0081]-[0090]).
Regarding claim 53, Whitfill teaches that the composition can be part of a kit for treating a skin disease that includes instructions for practicing the method ([0022]; [0074]-[0077]).
Claims 1, 4-6, 10, 14, 16, 19, 20, 38, 41, 44, 46, 50, 52 and 53 differ from Whitfill in that: the organism further comprises a coding sequence comprising a pro-peptide that is in-frame with the first and second coding sequences (claim 1); the organism is attenuated by auxotrophy (claim 4); the organism is a D-alanine auxotroph (claim 5); the promoter is P3 or SEQ ID 120 (claims 6 and 44); and the secretion peptide comprises SEQ ID 122 and/or the pro-peptide comprises SEQ ID 123 (claims 10 and 41).
Azitra teaches therapeutic compositions for treating skin diseases, comprising a recombinant microorganism, such as S. epidermidis, capable of secreting a therapeutic polypeptide, wherein the microorganism comprises, operably linked (in-frame), a first coding sequence comprising a nucleic acid sequence encoding the therapeutic polypeptide; a second coding sequence comprising a nucleic acid sequence encoding a secretion polypeptide; a third coding sequence comprising a nucleic acid sequence encoding a pro-peptide which can be LEISSTCDA (which is 100% identical to instant SEQ ID 123; p. 17, line 16) that assists with the export and/or folding of the exported protein; and a promoter which can be PyxiE (p. 19, line 9) (p. 2, line 19 to p. 6, line 15; p. 13, line 30 to p. 19, line 30). US20240166990 evidences that the PyxiE promoter comprises instant SEQ ID 120 (‘990 Example 1; see attached alignment of instant SEQ ID 120 vs. ‘990 SEQ ID 12). Azitra further teaches that the compositions can be formulated as topical compositions to be applied to the skin, similar to those of Whitfill (p. 19, line 23 to p. 27, line 3).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use a therapeutic composition for treating a skin disease comprising a microorganism capable of secreting a therapeutic LEKTI protein as taught by Whitfill wherein the microorganism further comprises a LEISSTCDA pro-peptide and/or a PyxiE promoter as taught by Azitra because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use a LEISSTCDA pro-peptide and/or a PyxiE promoter in a microorganism of Whitfill because Azitra teaches that the PyxiE promoter is a suitable promoter and that the pro-peptide can assist in export and/or folding of a therapeutic protein in a substantially similar composition as taught by Whitfill (comprising a probiotic microorganism, such as S. epidermidis, expressing a secreted therapeutic protein operably linked to a secretion peptide). Moreover, Le Loir evidences that inserting a LEISSTCDA pro-peptide in-frame with a signal peptide, as in the cited combination, significantly increases secretion levels (Le Loir, Abstract). Using a LEISSTCDA pro-peptide and/or a PyxiE promoter in a microorganism of Whitfill would have led to predictable results with a reasonable expectation of success because Azitra teaches use of the promoter and pro-peptide in a substantially similar composition as taught by Whitfill (comprising a probiotic microorganism, such as S. epidermidis, expressing a secreted therapeutic protein operably linked to a secretion peptide).
Regarding claims 4-5, Azitra teaches “A key requirement for nearly all recombinant microorganisms for clinical use is the ability to prevent undesired introduction to other individuals or environments. In order to ensure safety of the engineered strain, the present invention, In some embodiments, uses an auxotrophic strain, which requires supplementation of key amino acids (D-ala) … for survival, and simultaneously replaces the need for an antibiotic resistant strain for selection, the latter of which is not commercially viable.” (p. 38, lines 17-22). It would have been obvious to use a D-alanine auxotrophic strain in the composition of the cited combination for the reasons of safety and selection noted above, and one would have had a reasonable expectation of success in doing so because Azitra teaches use of such a strain in a substantially similar composition as taught by Whitfill.
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 1, 4-6, 10, 14, 16, 19, 20, 38, 41, 44, 46, 50, 52 and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,773,154 in view of US20190040116 to Whitfill et al. and WO2020206221 to Azitra.
The claims of the ‘154 Patent recite a recombinant probiotic microorganism, such as Streptococcus, capable of secreting a LEKTI-domain protein, comprising a (i) a first coding sequence comprising a nucleic acid sequence encoding the therapeutic polypeptide; and (ii) a second coding sequence comprising a nucleic acid sequence encoding a cell penetrating peptide. Whitfill and Azitra teach microorganisms for a substantially similar purpose of secreting a therapeutic peptide/LEKTI protein on the skin wherein the organism further comprises additional coding sequences encoding a secretion peptide and a pro-peptide, which can be LEISSTCDA (SEQ ID 123) (e.g., Whitfill, Tables 1-3; Azitra, p. 15, line 19 to p. 17, line 12; see also, 103 rejection above). Whitfill and Azitra further teach the dependent limitations, including D-alanine auxotrophy, the PyxiE promoter of SEQ ID 120, a kit with instructions and topical pharmaceutical formulations (see 103 rejection, above). The claims of the ‘154 patent thus render the instant claims obvious in view of Whitfill and Azitra.
Claims 1, 4-6, 10, 14, 16, 19, 20, 38, 41, 44, 46, 50, 52 and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 and 22 of copending Application No. 18/234588 in view of US20190040116 to Whitfill et al. and WO2020206221 to Azitra.
The ‘588 claims recite a recombinant microorganism, such as a Streptococcus bacteria, capable of expressing a LEKTI domain protein onto the skin of a subject (e.g., for treating Netherton syndrome), wherein the LEKTI protein is operably linked to a promoter and one or more sequences effective to enhance secretion and/or skin penetration of the LEKTI protein (‘588, claims 1-5, 13, 22).
Whitfill and Azitra teach microorganisms for a substantially similar purpose of secreting a therapeutic peptide/LEKTI protein on the skin wherein the organism further comprises additional coding sequences encoding a secretion peptide and a pro-peptide, which can be LEISSTCDA (SEQ ID 123) (e.g., Whitfill, Tables 1-3; Azitra, p. 15, line 19 to p. 17, line 12; see also, 103 rejection above). Whitfill and Azitra further teach the dependent limitations, including D-alanine auxotrophy, the PyxiE promoter of SEQ ID 120, a kit with instructions and topical pharmaceutical formulations (see 103 rejection, above). The claims of the ‘588 application thus render the instant claims obvious in view of Whitfill and Azitra.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4-6, 10, 14, 16, 19, 20, 38, 41, 44, 46, 50, 52 and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-63 of copending Application No. 19/288084 in view of US20190040116 to Whitfill et al. and WO2020206221 to Azitra.
The ‘084 claims recite a recombinant microorganism, such as a Streptococcus bacteria, capable of expressing a LEKTI domain protein and having D-alanine auxotrophy, as well as topical pharmaceutical compositions comprising such microorganism (‘084, claims 1, 11, 15, 19-21, 25). Whitfill and Azitra teach microorganisms for a substantially similar purpose of expressing a therapeutic peptide/LEKTI protein wherein the organism further comprises additional coding sequences encoding a secretion peptide and a pro-peptide, which can be LEISSTCDA (SEQ ID 123) (e.g., Whitfill, Tables 1-3; Azitra, p. 15, line 19 to p. 17, line 12; see also, 103 rejection above). Whitfill and Azitra further teach the dependent limitations, including the PyxiE promoter of SEQ ID 120 and a kit with instructions (see 103 rejection, above). The claims of the ‘084 application thus render the instant claims obvious in view of Whitfill and Azitra.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657