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’s election without traverse of Group III, stated to include claims 18, 20-22, 28, 30, 34 and new claims 35-46 in the reply filed on 8/30/23 is acknowledged.
Claims 23-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 8/30/23.
Applicant’s election without traverse of the species of polypeptide, SEQ ID NO:2, and the species of disease, prostate cancer, in the reply filed on 8/30/23 is acknowledged.
Applicant in the 8/30/23 reply, page 7, stated that the elected species are encompassed in claims 18, 20, 21, 28, 30, 35 and 43-46. However, claim 35, drawn to the method of claim 18 wherein X1 is alanine (SEQ ID NO:4), does not read on the elected SEQ ID NO:2 polypeptide, which has a valine at the corresponding position. Therefore claim 35 is withdrawn as being drawn to a nonelected species.
Claims 22, 34-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/30/23.
Claim Status
Claims 18, 22-27, 30, and 45 are pending.
Claims 1-17, 19-21, 28, 29, 31-44 and 46 are cancelled.
Claims 23-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 8/30/23.
Claims 22, 34-42 previously were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/30/23.
Claims 18, 30, and 45 are pending and under examination.
Claims 18, 30, and 45 are rejected.
Priority
The instant application, filed 02/04/2022 Claims Priority from Provisional Application 63/185503 , filed 05/07/2021.
Specification Objection
Applicant’s arguments, see page 7, filed 5/19/25, and title amendment, with respect to the specification objection have been fully considered and are persuasive. Therefore, that objection has been withdrawn. However, upon further consideration, a new ground(s) of specification objection is made in view of further narrowing of the claim 18 subject matter, which now does not include mellitin.
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: TREATING A CANCER WITH A POLYPEPTIDE CONSISTING ESSENTIALLY OF A SHORTENED FORM OF MELLITIN CONJUGATED TO A SPECIFIC d-FORM PEPTIDE.
Claim Interpretation – modified based on claim amendments
As amended 5/19/25, claim 18 is directed to a method of treating a cancer that is melanoma, prostate cancer, lung cancer, liver cancer, breast cancer, colon cancer or pancreatic cancer, to a subject in need thereof, this interpreted as being a human person or “nonhumans, including all animals, such as monkeys, dogs, goats, pigs, or mice”, see para 81, page 21. The treatment directed to these cancers limits the subjects to subjects that have any one of these cancers and are in need of treatment for one of these cancers. As instantly claimed such subjects are treated for any of the specifically recited cancers by administering a polypeptide consisting essentially of the amino acid of SEQ ID NO:2 conjugated to dKLA, the latter being a d-stereoisometric form of the peptide identified as KLA, which corresponds with SEQ ID NO:47 when in the l-stereoisometric form, claim 18 also stating “wherein the polypeptide targets M2 macrophages.”
Per the specification para 55, “The terms “polypeptide,” “peptide,” and “protein,” used interchangeably herein, refer to a polymeric form of amino acids of any length conjugated via an amide bond (or peptide bond). NH2 refers to the free amino group present at the amino terminus of a polypeptide. COOH refers to the free carboxyl group present at the carboxyl terminus of a polypeptide.”
The transition phrase “consisting essentially of” “limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention,” see MPEP 2111.03 III. As so amended, the administered polypeptide of claim 18 no longer encompasses full-length melittin conjugated to dKLA. This constitutes a substantial change in the breadth of what is claimed.
The examiner notes that at least Figure 19B indicates MpepK, this a species of what is claimed (Mpep (SEQ ID NO:2) attached to a linker (GGGS) (SEQ ID NO:36), which is attached to d-Lys-d-Leu-d-Ala-d-Lys-d-Leu-d-Ala-d-Lys-d-Lys-d-Leu-d-Ala-d-Lys-d-Leu-d-Ala-d-Lys (dKLA) (SEQ ID NO:47) per para 106, is effective to reduce tumor growth in a rodent model of prostate cancer.
Claim Rejections - 35 USC § 112 – Enablement
Claim 45 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 30, from which claim 45 depends, is directed to the method of claim 18, wherein the polypeptide (this comprising the amino acid of SEQ ID NO:2) is conjugated to the dKLA, another peptide, by a linker. The linker in the construct evaluated in the specification is GGGS, four amino acids, see paras 61, 106.
The functional groups of claim 45, such as carbodiimide, under normal organic syntheses to join together peptides or amino acids by forming a peptide bond, whether as a direct linking between the SEQ ID NO:2 comprising polypeptide and dKLA or when an intervening amino acid sequence such as GGGS is employed as the linker, are not found in the final product, which is what claim 30 is directed to.
For example, from www.thermofisher.com is found:
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Because the typical organic synthesis reaction removes the claimed carbodiimide functional group, and no other reaction was provided in the application as filed that resulted in such functional group remaining in the linked conjugate of claims 18 and 30, applicant is not enabled for the method of claim 45 for carbodiimide functional group, nor for any of the other functional groups listed based on their removal after reaction completion when reacting to form a peptide bond.
Claim Rejections - 35 USC § 102
Response to Arguments
Applicant’s arguments, see page 8, filed 5/19/25, and claim amendments, with respect to the rejection of claim(s) 18, 30 and 45 under 35 U.S.C. 102(a)(1) as being anticipated by Bae WO2019212324, have been fully considered and are persuasive. The rejection of claim(s) 18, 30 and 45 under 35 U.S.C. 102(a)(1) as being anticipated by Bae WO2019212324 has been withdrawn.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Response to Arguments
Applicant's arguments filed 5/19/25 have been fully considered but they are not persuasive.
Although applicant considers that it discovered that the SEQ ID NO:2 shortened form of mellitin, the latter taught to target M2 macrophages by Bae, to be a discovery worthy of patenting over the combined prior art, the examiner is not persuaded based on the established principles and applications of inherency as set forth in MPEP 2112. The provision of the Kim et al. reference by applicant reinforces Wickline’s teachings the its SEQ ID NO:88, identical to instant SEQ ID NO:2, has reduced toxicity and hemolytic effect when compared with the longer mellitin peptide.
Claim(s) 18 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over US 8617516, Wickline et al. (Wickline), in view of Lee et al., Jl for ImmunoTherapy of Cancer, 2019 7:147, 14 pages (Lee), as evidenced by Clin Cancer Res; 17(14) July 15, 2011 (GH, previously provided).
As amended 5/21/24, claim 18 is directed to a method of treating a cancer that is melanoma, prostate cancer, lung cancer, liver cancer breast cancer, colon cancer or pancreatic cancer, to a subject in need thereof, comprising administering a polypeptide consisting essentially of the amino acid of SEQ ID NO:2 conjugated to dKLA, the latter being a D-stereoisometric form of the peptide identified as KLA, which corresponds with SEQ ID NO:47, wherein the polypeptide targets M2 macrophages.
Wickline teaches a substantially non-lytic, non-cytotoxic anchor peptide that is capable of stably inserting into lipid membranes, and the invention provides nanoparticles comprising stably inserted anchor peptides, which may be conjugated to a variety of different cargo complexes, Abstract, emphasis added. The anchor peptide that may be utilized in applications to link a variety of cargo complexes to a nanoparticle and facilitate the delivery of the cargo complex to a cell, the cargo complexes may include therapeutic among other complexes, col. 5 lines 26-47. This approach overcomes previous problems and allows for a more generic construct that can be combined with specific targeting moieties for target delivery, see col. 1 lines 33-55 and col. 18, lines 5-12.
Example 8 teaches that NF-KB is a well-recognized target for anticancer treatment, para 129, and demonstrates that when the Nemo Binding Domain (NBD) inhibitory peptide is linked in a nanoparticle to the anchor peptide VLTTGLPALISWIKRKRQQ (also referred to as a linker peptide, para 133), with two glycines as a spacer, and added to F8 cells, the NBD-Linker incorporated PFC nanoparticles inhibited the nuclear translocation of the P65, NF-KB protein and at the higher the dose, less P65 was measured in the extracted nuclear protein (FIG. 19A), para 175.
The evidentiary reference GH, see Abstract, evidences that treating a cancer with NBD to inhibit NF-KB activity, resulting in reduced tumor burden, was recognized in the art.
Based on the teachings of Wickline, one of ordinary skill in the art at the time of the instant invention and before would have recognized that the NBD-Linker comprising the anchor/linker peptide VLTTGLPALISWIKRKRQQ, with two glycines as a spacer, was an effective therapy to administer to reduce NF-KB and thereby to treat a cancer through administering this as part of the indicated nanoparticles. Wickline claim 2, depending from its claim 1 nanoparticle claim, specifically states that the anchor peptide consists of SEQ ID NO:88, which is identical to instant SEQ ID NO:2.
Wickline also teaches that full-length melittin is cytotoxic and that a shorter peptide of melittin, its SEQ ID NO:88 corresponding to elected polypeptide SEQ ID NO:2 in its nanoparticles, this polypeptide being particularly claimed in claims 2 and 5, is taught to be substantially non-lytic, non-cytotoxic, so is a suitable anchor peptide capable of stably inserting into lipid membrane, Abstract, see also Examples 1-3, cols. 22-25. Wickline also taught its anchor peptides to be conjugated to a variety of different cargo complexes, col. 1 lines 23-29.
As to treating cancer, Wickline teaches that one objective of its invention pertains to targeted delivery of chemotherapeutic agents, where a targeting ligand can bind to a specific molecular epitope on the cell surface, in a nanoparticle, col. 1 lines 33-55, and teaches as an aspect of its invention the provision of a nanoparticle comprising an anchor peptide that is substantially non-lytic and non-cytotoxic, col 1 lines 59-63, thus providing a universal anchor peptide that would allow the pre-formed construction of carrier systems, see col. 1 lines 33-55. However Wickline is silent on its nanoparticles treating one of the claim 18 listed cancers.
Wickline also does not explicitly teach conjugating its SEQ ID NO:88, identical with instant SEQ ID NO:2, with a d-form of KLA, instant SEQ ID NO:47, and administering this to treat cancer.
The level of ordinary skill in the art is high and there is a strong motivation to modify therapeutic compounds to improve known approaches to treat a multitude of cancer types by improving the characteristics of one or more moieties of such compounds.
Lee teaches targeting of M2-like tumor-associated macrophages (TAMS, particularly CD206+ M-2 like TAMS) with a melittin-based pro-apoptotic peptide, Title, Abstract, Background, pages 1-2. Lee combines full-length mellitin with dKLA, and states this this MEL-dKLA induced selective cell death of M2 macrophages in vitro, Abstract/Results, and that this “could be used to target M2-like TAMS as a promising cancer therapeutic agent,” Abstract/Conclusion.
Lee, page 12, also teaches and suggests the following:
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Lee teaches that “The enhanced antitumor effects of combination therapy on checkpoint blockade with M2-like TAM targeting agents are repeatedly observed in solid tumor models such as lung cancer, colon cancer, melanoma, and especially in breast cancer,” page 12, so providing a very clear motivation to utilize MEL-dKLA, or dKLA with shorter forms of mellitin per the page 12 excerpt immediately above, to treat cancers including those listed in instant claim 18.
Wickline already teaches a shortened form of mellitin, SEQ ID NO:88, that has the above-indicated improvements over mellitin.
With regard to the added claim 18 wherein clause, wherein the polypeptide targets M2 macrophages, not only does Lee suggest “further applications of fragmented MEL derivatives” in the excerpt above, aligned with the objective to treat cancers and utilized as a drug carrier to target M2-like macrophages (see Title, Abstract, elsewhere), given the identity of Wickline SEQ ID NO:88 with instantly claimed SEQ ID NO:2, MPEP 2112 states, “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.” (bold emphasis added), and “… when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated.” That Wickline SEQ ID NO:88 is identical to instant SEQ ID NO:2 indicates that it has the same properties as instant SEQ ID NO:2, which includes the property of wherein the polypeptide targets M2 macrophages.
Additionally, based on the teachings and suggestions of Lee, including particularly as set forth in the excerpt above, there was a motivation to combine this shortened form, having known improvements over full length mellitin per Wickline, with dKLA, which Lee teaches is a cationic and amphiphilic alpha helix peptide that has a number of known properties including the induction of apoptosis, a desired property when using to target M2 macrophages in the tumor stroma, see page 2. The rationale is to improve cancer therapies by targeting M2 macrophages associated with a cancer tumor with a shortened form of mellitin known to have reduced off-target effects. There would have been a reasonable expectation of success given the combined teachings and data of Wickline and Lee, and the inherent property of targeting M2 macrophages when considering the inherent properties of identical peptides.
Accordingly, claim 18 would have been obvious.
Claim 30 would have been obvious because Lee teaches use of a GGGGS linker between its MEL (mellitin peptide sequence) and the dKLA, page 2, and additionally because Wickline Example 8 among other examples and paragraphs teaches linkers to join its anchor moieties including its SEQ ID NO:88 with different cargo complexes including therapeutically active compounds.
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.
Response to Arguments
Applicant's arguments filed 5/19/25 have been fully considered but they are not persuasive.
Applicant on page 11 argues that in view of the claim 18 amendment to recite “consisting essentially of” “thus does not read on the full length mellitin” and including because Bae “does not teach using the shortened form of mellitin, i.e., SEQ ID NO:2, to target M2 macrophages as instantly claimed in claim 18”, and including the 35 USC 103 arguments, the obviousness-type double patenting rejections be withdrawn.
These arguments are unpersuasive based on the rebuttals of the 35 USC 103 rejection as set forth above, including the 35 USC 103 rejections as they address inherency, and in view of the modifications made to the rejections below, necessitated by claim amendment.
Claims 18, 30, and 45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 7, 8, 9, 10, 14 and 17 of U.S. Patent No. 11484601 (reference patent, cited in 8/30/23 IDS), in view of US 8617516, Wickline et al. (Wickline) and Lee et al., Jl for ImmunoTherapy of Cancer, 2019 7:147, 14 pages (Lee), as evidenced by Clin Cancer Res; 17(14) July 15, 2011 (GH, previously provided).
As amended 5/21/24, claim 18 is directed to a method of treating a cancer that is melanoma, prostate cancer, lung cancer, liver cancer breast cancer, colon cancer or pancreatic cancer, to a subject in need thereof, comprising administering a polypeptide consisting essentially of the amino acid of SEQ ID NO:2 conjugated to dKLA, the latter being a D-stereoisometric form of the peptide identified as KLA, which corresponds with SEQ ID NO:47, wherein the polypeptide targets M2 macrophages.
Claim 30 depends from claim 18 and requires that the polypeptide is conjugated to the dKLA by a linker.
Reference patent claim 1 is directed to “a melittin-anticancer drug conjugate in which melittin is conjugated with an anticancer drug, the anticancer drug being a pro-apoptotic peptide selected from the group consisting of KLA, alpha-defensin-1, BMAP-28, brevenin-2R, buforin IIb, cecropin A-magainin 2 (CA-MA-2), cecropin A, cecropin B, chrysophsin-1, D-K6L9, gomesin, lactoferricin B, LLL27, LTX-315, magainin 2, magainin II-bombesin conjugate (MG2B), pardaxin and combinations thereof.”
Reference patent claim 3 further requires “wherein the conjugate targets an M2-type tumor-associated macrophage.”
Reference patent claim 5 further requires “wherein the melittin and the anticancer drug are conjugated to each other via a chemical linker, or the melittin and the anticancer drug are directly conjugated to each other.”
Reference patent claim 14 is directed to ”A method of preventing or treating a tumor-associated macrophage-mediated disease comprising administering the melittin-anticancer drug conjugate of claim 1 to a subject in need thereof.”
Reference patent claim 17 is directed to the “method of claim 14, wherein the tumor-associated macrophage-mediated disease is at least one selected from the group consisting of lung cancer, metastatic cancer, inflammatory disease, and breast cancer.”
Reference patent claims 7 and 8 pertain to chemical linkers, relevant to instant claim 45, and are lengthy so not reproduced herein.
Although the reference patent claims are directed to full-length mellitin peptide conjugated with an anti-cancer drug including KLA, and are directed to administering this to treat cancers including at least some of those listed in instant claim 18, the reference patent claims do not claim administering instant claim 1’s polypeptide consisting essentially of the amino acid of SEQ ID NO:2 (a shortened sequence of mellitin) conjugated to dKLA, the latter being a D-stereoisometric form of the peptide identified as KLA, which corresponds with SEQ ID NO:47, wherein the polypeptide targets M2 macrophages.
However, Wickline teaches a substantially non-lytic, non-cytotoxic anchor peptide that is capable of stably inserting into lipid membranes, and the invention provides nanoparticles comprising stably inserted anchor peptides, which may be conjugated to a variety of different cargo complexes, Abstract, emphasis added. The anchor peptide that may be utilized in applications to link a variety of cargo complexes to a nanoparticle and facilitate the delivery of the cargo complex to a cell, the cargo complexes may include therapeutic among other complexes, col. 5 lines 26-47. This approach overcomes previous problems and allows for a more generic construct that can be combined with specific targeting moieties for target delivery, see col. 1 lines 33-55 and col. 18, lines 5-12.
Example 8 teaches that NF-KB is a well-recognized target for anticancer treatment, para 129, and demonstrates that when the Nemo Binding Domain (NBD) inhibitory peptide is linked in a nanoparticle to the anchor peptide VLTTGLPALISWIKRKRQQ (also referred to as a linker peptide, para 133), with two glycines as a spacer, and added to F8 cells, the NBD-Linker incorporated PFC nanoparticles inhibited the nuclear translocation of the P65, NF-KB protein and at the higher the dose, less P65 was measured in the extracted nuclear protein (FIG. 19A), para 175.
The evidentiary reference GH, see Abstract, evidences that treating a cancer with NBD to inhibit NF-KB activity, resulting in reduced tumor burden, was recognized in the art.
Based on the teachings of Wickline, one of ordinary skill in the art at the time of the instant invention and before would have recognized that the NBD-Linker comprising the anchor/linker peptide VLTTGLPALISWIKRKRQQ, with two glycines as a spacer, was an effective therapy to administer to reduce NF-KB and thereby to treat a cancer through administering this as part of the indicated nanoparticles. Wickline claim 2, depending from its claim 1 nanoparticle claim, specifically states that the anchor peptide consists of SEQ ID NO:88, which is identical to instant SEQ ID NO:2 (found in instant claim 18).
Wickline also teaches that full-length melittin is cytotoxic and that a shorter peptide of melittin, its SEQ ID NO:88 corresponding to elected polypeptide SEQ ID NO:2 in its nanoparticles, this polypeptide being particularly claimed in claims 2 and 5, is taught to be substantially non-lytic, non-cytotoxic, so is a suitable anchor peptide capable of stably inserting into lipid membrane, Abstract, see also Examples 1-3, cols. 22-25. Wickline also taught its anchor peptides to be conjugated to a variety of different cargo complexes, col. 1 lines 23-29. This provides a motivation to modify the claimed conjugates of reference patent claim 1 to this shorter form to achieve a more favorable therapeutic compound that would be reasonably expected to have fewer off-target undesired effects.
As to treating cancer, Wickline teaches that one objective of its invention pertains to targeted delivery of chemotherapeutic agents, where a targeting ligand can bind to a specific molecular epitope on the cell surface, in a nanoparticle, col. 1 lines 33-55, and teaches as an aspect of its invention the provision of a nanoparticle comprising an anchor peptide that is substantially non-lytic and non-cytotoxic, col 1 lines 59-63, thus providing a universal anchor peptide that would allow the pre-formed construction of carrier systems, see col. 1 lines 33-55. However Wickline is silent on its nanoparticles treating one of the claim 18 listed cancers.
Wickline also does not explicitly teach conjugating its SEQ ID NO:88, identical with instant SEQ ID NO:2, with a d-form of KLA, instant SEQ ID NO:47, and administering this to treat cancer.
The level of ordinary skill in the art is high and there is a strong motivation to modify therapeutic compounds to improve known approaches to treat a multitude of cancer types.
Lee teaches targeting of M2-like tumor-associated macrophages (TAMS, particularly CD206+ M-2 like TAMS) with a melittin-based pro-apoptotic peptide, Title, Abstract, Background, pages 1-2. Lee combines full-length mellitin with dKLA, and states this this MEL-dKLA induced selective cell death of M2 macrophages in vitro, Abstract/Results, and that this “could be used to target M2-like TAMS as a promising cancer therapeutic agent,” Abstract/Conclusion.
Lee, page 12, also teaches and suggests the following:
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Lee teaches that “The enhanced antitumor effects of combination therapy on checkpoint blockade with M2-like TAM targeting agents are repeatedly observed in solid tumor models such as lung cancer, colon cancer, melanoma, and especially in breast cancer,” page 12, so providing a very clear motivation to utilize MEL-dKLA, or dKLA with shorter forms of mellitin per the page 12 excerpt immediately above, to treat cancers including those listed in instant claim 18.
Wickline already teaches a shortened form of mellitin, SEQ ID NO:88, that has the above-indicated improvements over the mellitin used in reference patent claim 1.
With regard to the added claim 18 wherein clause, wherein the polypeptide targets M2 macrophages (this already found, albeit referenced as a conjugate, in reference patent claim 3), not only does Lee suggest “further applications of fragmented MEL derivatives” in the excerpt above, aligned with the objective to treat cancers and utilized as a drug carrier to M2-like macrophages, given the identity of Wickline SEQ ID NO:88 with instantly claimed SEQ ID NO:2, MPEP 2112 states, “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.” (bold emphasis added), and “… when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated.” That Wickline SEQ ID NO:88 is identical to instant SEQ ID NO:2 indicates that it has the same properties as instant SEQ ID NO:2, which includes the property of wherein the polypeptide targets M2 macrophages.
Additionally, based on the teachings and suggestions of Lee, including particularly as set forth in the excerpt above, there was a motivation to combine this shortened form, having known improvements over full length mellitin per Wickline, with dKLA, which Lee teaches is a cationic and amphiphilic alpha helix peptide that has a number of known properties including the induction of apoptosis, a desired property when using to target M2 macrophages in the tumor stroma, see page 2. The rationale is to improve cancer therapies by targeting M2 macrophages associated with a cancer tumor with a shortened form of mellitin known to have reduced off-target effects. There would have been a reasonable expectation of success considering the above-noted reference patent claims and given the combined teachings and data of Wickline and Lee, and the inherent property of targeting M2 macrophages when considering the inherent properties of identical peptides.
Accordingly, claim 18 is rejected under this section.
Claim 30 also is rejected under this section not only based on the claiming of linkers in reference claims 7 and 8, as best understood, but also because Lee teaches use of a GGGGS linker between its MEL (mellitin peptide sequence) and the dKLA, page 2, and additionally because Wickline Example 8 among other examples and paragraphs teaches linkers to join its anchor moieties including its SEQ ID NO:88 with different cargo complexes including therapeutically active compounds.
Claim 45 also is rejected under this section based on reference patent claim 8 listing chemical linkers also found in instant claim 45, and the language of reference patent claims that reference patent claim 8 depends from.1
Claims 18 and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 9, 10, 12, 13 and 16 of U.S. Patent Application No. 18854337 (reference application), in view of Lee et al., Jl for ImmunoTherapy of Cancer, 2019 7:147, 14 pages (Lee).
As amended 5/21/24, claim 18 is directed to a method of treating a cancer that is melanoma, prostate cancer, lung cancer, liver cancer breast cancer, colon cancer or pancreatic cancer, to a subject in need thereof, comprising administering a polypeptide consisting essentially of the amino acid of SEQ ID NO:2 conjugated to dKLA, the latter being a D-stereoisometric form of the peptide identified as KLA, which corresponds with SEQ ID NO:47, wherein the polypeptide targets M2 macrophages.
Claim 30 depends from claim 18 and requires that the polypeptide is conjugated to the dKLA by a linker.
In Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co., 95 USPQ2d 1797 (Fed. Cir. 2010), the Court determined that claims of a later patent were held invalid for obviousness-type double patenting when the earlier patent claimed a compound and disclosed its utility in specification, and later patent claimed a method of using compound for use described in specification of earlier patent.
Here, the later-filed reference application claim 1 is directed to a pharmaceutical composition for removing tumor-associated macrophages (TAMs) in a tumor microenvironment, comprising as an active ingredient a conjugate in which a pro-apoptotic peptide or an anticancer drug is conjugated to melittin, a variant thereof, or analogues thereof, reference application claim 6’s variant of mellitin includes the amino acid sequence of its SEQ ID NO:2 which is identical with instantly claimed SEQ ID NO:2 of instant claim 18, reference application claim 9 is directed to the pharmaceutical composition of claim 1, wherein the pharmaceutical composition includes a peptide including an amino acid sequence of SEQ ID NO: 5 or 6, SEQ ID NO:6 is VLTTGLPALISWIKRKRQQGGGGSKLAKLA KKLAKLAK, which comprises instant SEQ ID NO:2, VLTTGLPALISWIKRKRQQ, linked by the GGGGS linker to KLA, this the same as instant SEQ ID NO:47, Lys Leu Ala Lys Leu Ala Lys Lys Leu Ala Lys Leu Ala Lys. So the reference applications combination of claims 1 and 9 are directed to the same instant SEQ ID NO:2 conjugated to a KLA, but the KLA of the reference application is not in the D-form.
Also, reference application claim 10 lists KLA among a list of pro-apoptotic peptides, and reference application claim 13 lists types of cancers that the pharmaceutical composition of claim 12 (this including a variant of mellitin in a conjugate also including a pro-apoptotic peptide) that are also listed in instant claim 18.
Please also note that reference application claim 16 is directed to a method for treating cancer, comprising administering to a subject suffering from cancer a pharmaceutically effective amount of a conjugate in which a pro-apoptotic peptide or an anticancer drug is conjugated to melittin, a variant thereof, or analogues thereof, so that it would have been obvious to administer the reference application claim 9 when practicing the reference application claim 16 method.
Based on the above, the reference application claims include a method for treating cancer in a subject suffering from cancer so in need of treatment, of cancers per reference claim 13 including cancers listed in instant claim 18, including with instant SEQ ID NO:2 conjugated to KLA, however does not explicitly specify that its polypeptides targets M2 macrophages, nor that dKLA is conjugated to the SEQ ID NO:2 peptide.
As to the bases for making modifications of the above-noted claimed subject matter to arrive at using a d-form of KLA, and as to the instant claim 18 polypeptide targeting M2 macrophages, the following references’ teachings are applied.
Lee teaches targeting of M2-like tumor-associated macrophages (TAMS, particularly CD206+ M-2 like TAMS) with a melittin-based pro-apoptotic peptide, Title, Abstract, Background, pages 1-2. Lee combines full-length mellitin with dKLA, and states this this MEL-dKLA induced selective cell death of M2 macrophages in vitro, Abstract/Results, and that this “could be used to target M2-like TAMS as a promising cancer therapeutic agent,” Abstract/Conclusion, emphases added.
Lee, page 12, also teaches and suggests the following:
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Lee teaches that “The enhanced antitumor effects of combination therapy on checkpoint blockade with M2-like TAM targeting agents are repeatedly observed in solid tumor models such as lung cancer, colon cancer, melanoma, and especially in breast cancer,” page 12, so providing a very clear motivation to utilize MEL-dKLA, or dKLA with shorter forms of mellitin per the page 12 excerpt immediately above, to treat cancers including those listed in instant claim 18 (already found in the reference patent claim 13).
Reference claims 6 and 9 already claim the shortened form of mellitin, identified as SEQ ID NO:2 in the instant claim 18 and the reference application claim 6, and in claim 9 combine this with KLA.
Lee, page 2, teaches that “The all-D enantiomer form of amino acids was used for the KLA sequence to avoid degradation by proteases in vivo,” this providing a motivation to substitute the dKLA of Lee for the standard (presumably L-form) KLA of the reference claims. There would have been a reasonable expectation of success, and improvement, based on this teaching from Lee. Based on Lee’s reason for using dKLA (rather than KLA), there is a motivation to substitute that KLA with dKLA, which Lee also teaches is a cationic and amphiphilic alpha helix peptide that has a number of known properties including the induction of apoptosis, a desired property when using to target M2 macrophages in the tumor stroma, see page 2. The rationale is to improve cancer therapies by targeting M2 macrophages associated with a cancer tumor with a shortened form of mellitin already claimed in the reference claims. There would have been a reasonable expectation of success considering the above-noted reference patent claims and given the combined teaching and data of Lee (and also the inherent property of targeting M2 macrophages when considering the inherent properties of identical peptides, see above).
Accordingly, claim 18 is rejected under this section.
Claim 30 also is rejected under this section not only based on the specific GGGGS linker in reference claim 9’s SEQ ID NO:6, positioned per above between SEQ ID NO:2 and KLA, and also because Lee teaches use of a GGGGS linker between its MEL (mellitin peptide sequence) and the dKLA, page 2.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/JOSEPH FISCHER/Examiner, Art Unit 1658
1 Please note that the language set forth in reference claims 5, 7 and 8 do not present the same problems identified in instant claim 45 that necessitated the above 35 USC 112 enablement rejection.