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 .
Election/Restrictions
Applicant elected Group I, without traverse, in the reply filed on 3/20/2026.
Claims 2, 6, 9, 14, 20, 22, 24-25, 41, 44, and 70-74 have been canceled while claims 75-94 have been added, which are directed to the treatment method of Group I. Hence, claims 75-94 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/GB2021/050783 filed on 3/30/2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 9/26/2023, 1/15/2025, 7/15/2025, and 3/20/2026 are in compliance with the provisions of 37 C.F.R. 1.97. Accordingly, all references cited in these IDSs have been fully considered.
Drawings
The drawings are objected to because of improper labels: (i) Figure 4 has four illustrations presented in four pages, the last three of which are labeled as “FIGURE 4 CONTINUED”; (ii) Figure 5 has three illustrations shown in three pages in which the last two are also labeled as “FIGURE 5 CONTINUED”; (iii) Figure 6 has four illustrations presented in four pages, the last three of which are labeled as “FIGURE 6 CONTINUED”; and (iv) Figure 7 has two illustrations and the second one is labeled as “FIGURE 7 CONTINUED”. According to 37 C.F.R. 1.84(u)(i), “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.””. See MPEP § 608.02(V).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
In addition to Replacement Sheets containing the corrected drawing figure(s), applicant is required to submit a marked-up copy of each Replacement Sheet including annotations indicating the changes made to the previous version. The marked-up copy must be clearly labeled as “Annotated Sheets” and must be presented in the amendment or remarks section that explains the change(s) to the drawings. See 37 CFR 1.121(d)(1). Failure to timely submit the proposed drawing and marked-up copy will result in the abandonment of the application.
Claim Objections
Claim 91 is objected to because of the following informality: unnecessary use of the conjunction “or” before “a central neuropathy” in (b). Appropriate correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 75-81 and 89-91 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ichtchenko et al. (Pub. No. WO 2021/067466 A1).
Ichtchenko et al. discloses a recombinant Clostridium botulinum neurotoxin having a 2-20 fold reduced toxicity compared to wild type C. botulinum neurotoxin, as well as a method of using said recombinant C. botulinum neurotoxin (Abstract).
According to Ichtchenko et al., the endopeptidase activity responsible for Clostridial neurotoxin toxicity is associated with the presence of a HExxHxxH motif in the light chain, characteristic of metalloproteases. Site-directed mutagenesis of BoNT A light chain pinpointed the amino acid residues involved in Zn2+ coordination, and formation of the active metalloendoprotease core which cleaves SNAP-25. The three-dimensional structures of Clostridial neurotoxins and their derivatives confirmed the mutagenesis results. Based on these findings, modified toxin genes with properties specifically altered for therapeutic goals can be designed (par. [0041]).
Thus in an embodiment, the C. botulinum neurotoxin has a metalloprotease disabling mutation (par. [0042]). The metalloprotease disabling mutation can be Y366>X of BoNT A, where X is an amino acid that causes minimal structural interference to the light chain protease such as phenylalanine (par. [0043]). Alternatively, the disabling mutation corresponds to E224>X of BoNT A, i.e., the glutamate at a position corresponding to 224 of BoNT A1 is substituted for glutamine (E224Q) (par. [0044]-[0045]).
In other embodiments, the C. botulinum neurotoxin is selected from BoNT serotype B1 (BoNT B) with a mutation of E231 >X, BoNT serotype Cl (BoNT C) with a mutation of E230 >X, BoNT serotype D (BoNT D) with a mutation of E230 >X, BoNT serotype El (BoNT E) with a mutation of E213 >X, BONT serotype FI (BoNT F) with a mutation of E228 >X, BoNT serotype G (BoNT G) with a mutation of E233 >X, BoNT serotype H (BoNT H) with a mutation of E227 >X, and BoNT serotype X (BoNT X) with a mutation of E228 >X (par. [0044]).
To use the recombinant C. botulinum neurotoxin, Ichtchenko et al. teaches methods comprising administering the C. botulinum neurotoxin to a subject (par. [0098]), wherein the subject includes humans and non-human primates (par. [0105]). Examples of applicable administration routes include parenteral administration (par. [0098]).
The methods can be utilized to control pain or treat amputation pain, pain after mastectomy, chest pain of esophageal origin, headache, neurogenic pain like arthritis, chronic temporomandibular joint (TMJ) pain, and pain associated with conditions characterized by sensitization of nociceptors (par. [0110]-[0111]; claim 8).
Ichtchenko et al.’s method reads on the instant application’s method as follows:
Regarding claim 75: administering the disclosed recombinant C. botulinum neurotoxin to a subject (par. [0098]) in order to control or treat pain (par. [0110]-[0111]; claim 8) is equivalent to “A method for treating pain, the method comprising administering a clostridial neurotoxin to a subject”.
The recombinant C. botulinum neurotoxin comprising a light chain of a C. botulinum neurotoxin and a heavy chain of a C. botulinum neurotoxin (par. [0024], [0027]), wherein the heavy chain comprises a translocation domain and a receptor binding domain as shown, for example, by a BoNT A having a mutation of E224>Q (SEQ ID NO: 25; par. [0091]) in the graphic summary below, meets “wherein the clostridial neurotoxin comprises a light chain, a translocation domain (HN domain) and/or a receptor binding domain (Hc domain)”.
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The embodiment of the recombinant C. botulinum neurotoxin having a metalloprotease disabling mutation, which results in loss of enzymatic activity (par. [0041]-[0042]), satisfies “wherein the light chain is catalytically inactive”.
Regarding claim 76: the metalloprotease disabling mutation corresponding to E224>Q or Y366>F in BoNT A fulfills “wherein the clostridial neurotoxin comprises a botulinum neurotoxin A (BoNT/A) and wherein the BoNT/A light chain comprises one or more mutations at positions H223, E224, H227, E262, R363 and/or Y366”.
Regarding claim 77: the E224>Q mutation is the same as “wherein the BoNT/A light chain comprises a mutation at E224 and/or H227”.
Regarding claim 78: the E224>Q mutation has the glutamate (E) at position 244 of BoNT A1 substituted with glutamine (Q) and thus meets “wherein the BoNT/A light chain comprises E224Q and/or H227Y”.
Regarding claim 79: sequence-to-sequence alignment of the prior art’s SEQ ID NO: 25 with applicant’s SEQ ID NO: 62 demonstrates that they are 98.6% identical, thereby satisfying “wherein the BoNT/A is catalytically inactive and comprises at least 90% identity to SEQ ID NO: 62”.
Regarding claim 80: the C. botulinum neurotoxin can be selected from BoNT B with a mutation of E231 >X, BoNT C with a mutation of E230 >X, BoNT D with a mutation of E230 >X, BoNT E with a mutation of E213 >X, BoNT F with a mutation of E228 >X, BoNT G with a mutation of E233 >X, BoNT H with a mutation of E227 >X, and BoNT X with a mutation of E228 >X (par. [0044]).
This teaching fulfills the limitation “wherein the clostridial neurotoxin is a botulinum neurotoxin comprising:(a) a BoNT/B light chain comprising one or more mutations at positions E231 and/or H234;(b) a BoNT/C light chain comprising one or more mutations at positions H229, E230 and/or H233;(c) a BoNT/D light chain comprising one or more mutations at positions H229, E230, H233 and/or H236; (d) a BoNT/E light chain comprising one or more mutations at positions E213 and/or H216; (e) a BoNT/F light chain comprising one or more mutations E228 and/or H231; (f) a BoNT/G light chain comprising one or more mutations E231 and/or H234; or (g) a BoNT/X light chain comprising one or more mutations E228 and/or H231”.
Regarding claim 81: the disclosed metalloprotease disabling mutations (par. [0044]) are the same as some of the recited mutations:
Ichtchenko et al.’s metalloprotease disabling mutations
Claim limitation
E231 >Q in BoNT B1
(a) a BoNT/B light chain comprising one or more mutations E231Q and/or H234Y;
E230 >Q in BoNT C1
(b) a BoNT/C light chain comprising one or more mutations H229G, E230T and/or H233N;
E230 >Q in BoNT D
(c) a BoNT/D light chain comprising one or more mutations E230Q and/or H236Y;
E213 >Q in BoNT E1
(d) a BoNT/E light chain comprising one or more mutations E213Q and/or H216Y;
E228 >Q in BoNT F1
(e) a BoNT/F light chain comprising one or more mutations E228Q and/or H231Y;
E231 >Q in BoNT G
(f) a BoNT/G light chain comprising one or more mutations E231Q and/or H234Y; or
E228 >Q in BoNT X
(g) a BoNT/X light chain comprising one or more mutations E228Q and/or H231Y
Regarding claim 89: controlling or treating pain such as pain after mastectomy, which is an acute type of pain, as well as arthritis and chronic temporomandibular joint (TMJ) pain, which are chronic type of pain, is equivalent to “wherein the pain is chronic pain or acute pain”.
Regarding claim 90: examples of pain being treated include headache and neurogenic pain (also known as neuropathic pain), thereby satisfying “wherein the pain is bladder pain, inflammatory pain, neuropathic pain, mixed pain, allodynia, visceral pain, headache pain, migraine, post-operative pain, referred pain, somatic pain, or phantom limb”.
Regarding claim 91: treating neurogenic pain and inflammation like arthritis and TMJ pain (which is a repetitive motion disorder) corresponds to “wherein: (a) the inflammatory pain is caused by or associated with… an arthritic disorder… (e) the somatic pain is caused by or associated with… a repetitive motion disorder”.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 75-83 and 89-91 are rejected under 35 U.S.C. 103 as being unpatentable over Ichtchenko et al. (Pub. No. WO 2021/067466 A1) in view of Yuan et al. (Pub. No. CN 109776660 A; English translation).
Ichtchenko et al.’s teachings are set forth above and applied herein. This prior art is found to anticipate claims 75-81 and 89-91.
The method of Ichtchenko et al. is comparable to the claims below:
Regarding claim 82: the clostridial neurotoxin in the method of claim 75 is further required to comprise “a tetanus neurotoxin light chain comprising one or more mutations E234, R372 and/or Y375”.
Ichtchenko et al. is different from the instant claim in that the disclosed method does not use tetanus neurotoxin.
Nonetheless, it is known in the art that tetanus neurotoxin (TeNT) is another neurotoxin produced by Clostridium bacteria (par. [0003]). Like botulinum neurotoxins (BoNTs), TeNT is synthesized as a single chain protein that is cleaved into a light chain and a heavy chain comprising an N-terminal domain and a C-terminal domain, wherein the light chain is a zinc-dependent protease with Y375 as a catalytically active site, as substantiated by Yuan et al. (first par., page 2). TeNT and BoNTs work by cleaving SNARE proteins, thereby blocking the release of neurotransmitters and inhibiting signal transmission. Yuan et al. states that previous studies found that mutating the arginine at position 372 to alanine and the tyrosine at position 375 to phenylalanine leads to inactivating the zinc-dependent metalloprotease activity, which render the neurotoxin non-toxic but still keep its activity.
Since tetanus neurotoxin is a recognized equivalent to BoNTs and mutations at amino acid positions 372 and 375 make the neurotoxin non-toxic, a person with ordinary skill in the art before the effective filing date of the claimed invention would have been motivated by Yuan et al. to use tetanus neurotoxin having R372A and Y375F mutations in Ichtchenko et al.’s method and expect that this modification would improve safety. Obviousness is established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so. See MPEP § 2143.01 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
Thus, claim 82 is obvious over Ichtchenko et al. in view of Yuan et al..
Regarding claim 83: the tetanus neurotoxin light chain in the method of claim 82 is additionally specified to comprise “one or more mutations R372Q or R372A, and/or Y375F”, which is fulfilled by the modified method’s use of tetanus neurotoxin comprising R372A and Y375F mutations in the light chain.
Claims 75-81, 84-85, and 89-91 are rejected under 35 U.S.C. 103 as being unpatentable over Ichtchenko et al. (Pub. No. WO 2021/067466 A1) in view of Liu (Pub. No. US 2019/0127427 A1; IDS-cited).
The teachings of Ichtchenko et al. are described previously and applied herein. Ichtchenko et al. anticipates claims 75-81 and 89-91.
Ichtchenko et al.’s method is similar to the following claims:
Regarding claim 84: the clostridial neurotoxin is defined as “a chimeric botulinum neurotoxin (BoNT) comprising a BoNT/A light chain and translocation domain, and a BoNT/B receptor binding domain”.
Ichtchenko et al. differs from the instant claim in that it only teaches using a derivative of a C. botulinum neurotoxin made of a light chain from one serotype like BoNT A1 and a heavy chain from another serotype such as BoNT B1 (lines 1-7, page 7).
Chimeric neurotoxins for use in therapy, however, are known in the art. For instance, Liu provides a chimeric neurotoxin comprising a light chain and translocation domain (LHN) from a first neurotoxin linked to a receptor binding domain (HC) from a second neurotoxin, wherein the first and second neurotoxins are different (par. [0017], [0030]-[0032]). The first and second neurotoxins can be modified such as in the amino acid sequence of the light chain (par. [0104]-[0108]). In a preferred embodiment, the first neurotoxin is BoNT serotype A and the second neurotoxin is serotype B. Examples of BoNT/AB include chimeric neurotoxins comprising the amino acid sequence of SEQ ID NO: 12 or 13 (par. [0118]-[0119] and [0125]; “Chimera 3B” or “Chimera 3C” in Table 3, par. [0179]). Liu’s chimeric neurotoxin can be employed to treat a condition associated with unwanted neuronal activity in a subject in need thereof by administering an effective amount of the chimeric neurotoxin to said subject. The condition is selected from a group that includes pain from muscle spasms, headache pain, and migraine (par. [0145]).
A person with ordinary skill in the art before the effective filing date of the claimed invention would have replaced the recombinant botulinum neurotoxin in Ichtchenko et al.’s method with a chimeric neurotoxin comprising a LHN from BoNT A that has a metalloprotease disabling mutation and a HC from BoNT B with reasonable expectation that said chimera would still be able to treat pain in a subject. Obviousness is based on the rationale that simple substitution of one known element for another yields nothing more than predictable results. See MPEP § 2143.01 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
Claim 84 is therefore obvious over Ichtchenko et al. in view of Liu.
Regarding claim 85: the chimeric neurotoxin in the method of claim 84 is further stipulated to be “catalytically inactive and comprises at least 90% identity to SEQ ID NO: 61”. Given that Liu’s Chimera 3B and Chimera 3C are 99.9% and 99.6% identical to applicant’s SEQ ID NO: 61, a chimeric neurotoxin comprising a LHN from BoNT A that has a metalloprotease disabling mutation in one amino acid position (E224>Q or Y366>F) and a HC from BoNT B is expected to have catalytically inactive and at least 90% identical to SEQ ID NO: 61.
Claims 75-81, 86-87, and 89-93 are rejected under 35 U.S.C. 103 as being unpatentable over Ichtchenko et al. (Pub. No. WO 2021/067466 A1) in view of Dong et al. (Pub. No. US 2022/0220466 A1).
Ichtchenko et al.’s teachings are discussed above and applied herein. This prior art is found to anticipate claims 75-81 and 89-91.
Ichtchenko et al.’s method is comparable to the claims below:
Regarding claim 86: the clostridial neurotoxin is additionally limited to be a “chimeric botulinum neurotoxin comprising a BoNT/X light chain and translocation domain, and a BoNT/B receptor binding domain”.
Ichtchenko et al. does not teach utilizing a chimeric botulinum.
Use of chimeric botulinum neurotoxin for therapeutic applications is known in the art. Dong et al., for example, discloses catalytically inactive toxin chimeras derived from C. botulinum toxin serotype X and using them to treat a disease (Abstract). The catalytically inactive toxin chimeras comprise (a) a light chain comprising an inactive protease domain and (b) a heavy chain comprising (i) a translocation domain from a neurotoxin in C. botulinum serotype X, as well as (ii) a receptor domain from a BoNT produced by C. botulinum serotype A, B, C, D, E, F, G, or H (par. [0008]-[0012], [0100]). An example is BoNT/XB having the amino acid sequence of SEQ ID NO: 24 (Table 2, page 56). Dong et al. teaches that the disclosed catalytically inactive toxin chimeras are useful for treating a neurological condition including pain from muscle spasms and headache pain (par. [0256]). Accordingly, one with ordinary skill in the art before the effective filing date of the claimed invention would have substituted the recombinant botulinum neurotoxin in Ichtchenko et al.’s method with one of Dong et al.’s catalytically inactive toxin chimeras such as BoNT/XB and predict that it would still be effective in treating pain in a subject. Simple substitution of one known element for another yields predictable results. See MPEP § 2143.01 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
Hence, claim 86 is obvious over Ichtchenko et al. in view of Dong et al..
Regarding claim 87: the chimeric neurotoxin (BoNT/XB (0)) in the method of claim 86 is further required to be “catalytically inactive and comprises at least 90% identity to SEQ ID NO: 64”. This limitation is met by Dong et al.’s BoNT/XB (SEQ ID NO: 24), which is 99.1% identical to applicant’s SEQ ID NO: 64.
Regarding claim 92: the clostridial neurotoxin is specified to be “administered at a dose between 250 µg to 1000 µg”.
Although Ichtchenko et al. does not teach the amount of recombinant C. botulinum neurotoxin that is administered, Dong et al. teaches that the appropriate dose of a catalytically inactive toxin depends on various factors including the specific agent, formulation, route of administration, type and severity of disease being treated. A person with ordinary skill in the art would have therefore found the claimed dose via routine experimentation and optimization. Furthermore, Dong et al. teaches that the dose for an adult subject of normal weigh can range from about 0.01 to 1000 mg/kg so the dose can be between 1 to 200 mg, which corresponds to 1,000 to 200,000 µg (par. [0243]-[0244]).
Regarding claim 93: the clostridial neurotoxin is necessitated to be “administered intradermally”.
Ichtchenko et al. only teaches administering the recombinant C. botulinum neurotoxin parenterally (par. [0098]) but not intradermally in particular.
Parenteral administration techniques like intradermal administration are well-known and conventional in the art. For example, Dong et al. teaches treating a disease through parenteral administration of an inactive BoNT such as by intradermal injection (par. [0240]). One with ordinary skill in the art would have administered the recombinant C. botulinum neurotoxin to a subject via the known technique of intradermal injection and predict that said neurotoxin would be successfully delivered. Applying a known technique to a known method ready for improvement yields predictable results.
Claims 75-81, 88-91, and 94 are rejected under 35 U.S.C. 103 as being unpatentable over Ichtchenko et al. (Pub. No. WO 2021/067466 A1) in view of Kupinski et al. (Pub. No. WO 2020/065336 A1; IDS-cited).
The teachings of Ichtchenko et al. are set forth above and applied herein. This prior art is found to anticipate claims 75-81 and 89-91.
Ichtchenko et al.’s method is similar to the following claims:
Regarding claim 88: the clostridial neurotoxin is further stipulated to comprise “an activation loop of any one of SEQ ID NO: 71-73 or 78”.
Ichtchenko et al. differs from the instant claim in that the disclosed recombinant C. botulinum neurotoxin does not have an activation loop comprising any of the recited amino acid sequences.
Nevertheless, clostridial neurotoxins are known to be expressed as single chain polypeptides that have to be cleaved at the activation loop to separate the light chain from the heavy chain and form a fully active di-chain toxin as substantiated by Kupinski et al. (lines 21-27, page 1). Kupinski et al. teaches that this activation process must be reproduced during recombinant toxin production. But for some clostridial toxins, cleavage by an exogenous protease like trypsin or Lys-C is incomplete or improper and necessitates purification of the di-chain polypeptide (lines 29-27, page 7). To overcome this problem, Kupinski et al. teaches replacing an endogenous activation loop in a clostridial neurotoxin with an exogenous activation loop comprising the sequence Cys-(Xaa)a-Ile-Asp/Glu-Gly-Arg-(Yaa)b-Cys (SEQ ID NO: 1; lines 11-14, page 3). Such clostridial neurotoxin is suitable for treatment of a disease or condition like tension headache, muscle pain, and headache pain (lines 32-33, page 44; lines 6-7 and 11, page 45). It would have thus been obvious for a person with ordinary skill in the art to modify Ichtchenko et al.’s method by replacing the endogenous activation loop in the disclosed recombinant C. botulinum neurotoxin with Kupinski et al.’s activation loop comprising SEQ ID NO: 1 (which is 100% identical to applicant’s SEQ ID NO: 1) and expect that such modification would provide the benefit of completely and properly activating the neurotoxin, which can be utilized to treat pain. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP § 2143.01 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
Claim 88 is thus obvious over Ichtchenko et al. in view of Kupinski et al..
Regarding claim 94: the clostridial neurotoxin is specified to be “retargeted and comprises a non-clostridial targeting moiety”.
Ichtchenko et al. does not teach the limitations of the instant claim.
Re-targeting is known in the art as shown by Kupinski et al.. Kupinski et al. teaches that a targeting moiety provides binding specificity for a desired target cell. By engineering a clostridial neurotoxin with a targeting moiety such that the native binding portion is removed, the clostridial neurotoxin can be re-targeted (lines 18, page 38; claims 13-15). Accordingly, a person with ordinary skill in the art would have incorporated a targeting moiety to the disclosed recombinant C. botulinum neurotoxin with reasonable expectation that the resulting neurotoxin would be re-targeted. Obviousness is based on the rationale that combining prior art elements according to known methods yields predictable results.
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 75-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 96 and 103-111 of co-pending Application No. 18/552788.
The co-pending application is drawn to a method for treating pain or an inflammatory disorder. The method comprises administering a polypeptide to a subject, wherein the polypeptide comprises:
(a) at least one of the following:
(i) a catalytically inactive clostridial neurotoxin L-chain,
(ii) a clostridial neurotoxin HN domain, and/or
(iii) a clostridial neurotoxin HC domain; or
(b) a clostridial neurotoxin L-chain and lacks a functional HCC domain or HC domain of a clostridial neurotoxin.
In one embodiment, the polypeptide is a chimeric BoNT comprising a catalytically inactive BoNT/A L-chain and HN domain, and a HC domain from BoNT/B. Moreover, the polypeptide can comprise a sequence having at least 70% sequence identity to any of the recited SEQ ID NOs, which includes SEQ ID NO: 2 having mutations at positions 224 (Q) and 227 (Y) (99.5% identical to instant application’s SEQ ID NO: 62) and SEQ ID NO: 10 having mutations at positions 231 (Q) and 234 (Y).
In another embodiment, the polypeptide is a chimeric BoNT comprising a catalytically inactive BoNT/X L-chain and HN domain, and a HC domain from a different clostridial neurotoxin. The polypeptide can have at least 70% sequence identity to any of the recited SEQ ID NOs including SEQ ID NO: 61 (100% identical to instant application’s SEQ ID NO: 61) and SEQ ID NO: 64 (100% identical to instant application’s SEQ ID NO: 64). The polypeptide can also comprise Cys-Xaa-Ile-Asp/Glu-Gly-Arg-Yaa-Cys (which is an activation loop having the same amino acid sequence as the instant application’s SEQ ID NO: 71).
The pain being treated can be chronic pain or acute pain. In one embodiment, it is limited to bladder pain, inflammatory pain, neuropathic pain, mixed pain, allodynia, visceral pain, headache pain, post-operative pain, referred pain, somatic pain, or phantom limb pain. To treat the pain or inflammatory disorder, the polypeptide is administered iteratively or intradermally. In an embodiment, the dose being administered is 250 µg or greater.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE F PAGUIO FRISING whose telephone number is (571)272-6224. The examiner can normally be reached Monday-Friday, 8:00 a.m. - 4:00 p.m..
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/Michelle F. Paguio Frising/Primary Examiner, Art Unit 1651
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