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 .
Claim Status
Claims 1, 4-12 and 14-20 are pending.
Claims 2-3 and 13 have been canceled.
Claims 7 and 9-12 are withdrawn.
Claims 1 and 18 are currently amended.
Claims 1, 4-6, 8 and 14-20 are currently under consideration.
Claims 1, 4-6, 8 and 14-20 are rejected.
Acknowledgement of Receipt
This Office Action is in response to the Applicants’ amendments and remarks filed 01/20/2026.
Withdrawn Objections/Rejections
The objection to claim 1 is withdrawn.
Upon further consideration, rejection of claim 18 under 35 U.S.C. 112(b) is withdrawn.
In light of the new amendments, the rejection of claims 1, 4-5, 13, 16 and 19-20 under 35 U.S.C. 102 as being anticipated by Ishikawa evidenced by Herchel and NCI is withdrawn.
New Rejections
Applicant’s amendments have necessitated the following grounds of rejection:
Claim Rejections - 35 USC § 103
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 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. Applicants are 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.
Applicant Claims
The instant claims are directed to a self-assembled complex containing an iron ion, consisting of: an iron ion; at least one ligand; and an active ingredient supported in the self-assembled complex, wherein the iron ion and the ligand are reversibly self-assembled or self-disassembled, wherein the iron ion and the ligand are self-assembled to form an assembled structure, and wherein the active ingredient is triamcinolone acetonide, and wherein the self-assembled complex comprises π-π interaction and hydrogen bonding between the ligands; wherein the active ingredient is released through self-disassembly of the self-assembled complex, the active ingredient being released continuously over a release time that is 1 to 90 days; wherein in the ligand is ATP (elected), wherein the self-assembled complex is hydrophilic, wherein the iron ion and the ligand are included at a molar concentration ratio of 5:1 to 1:1.
Applicants further claim that the rate of self-disassembly varies by the type of the ligand, wherein the self-assembled complex is self-disassembled over 1 to 90 days; wherein self-disassembly is accelerated under accelerating conditions with at least any one of a chelating agent, a strong acid, and a strong base compared to non-accelerating conditions without the chelating agent, the strong acid, or the strong base, wherein the condition with a strong acid has a pH of 2 to 5, wherein the condition with a strong base has a pH of 9 to 12; wherein self-disassembly is accelerated under accelerating conditions compared to non-accelerating conditions to have a duration of 0.5 second to one minute; wherein the self-assembled complex is paramagnetic, wherein magnetic moment increases with an increase in the size of the self-assembled complex; wherein when a magnetic field is applied to the self-assembled complex in vivo or in vitro, the larger the self-assembled complex, the more quickly it spreads.
Claims 1, 4-5, and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ishikawa (US 10,034,851 B2) evidenced by Herchel (The Royal Society of Chemistry, Dalton Trans., 2009, 9870–9880) and National Cancer Institute (NCI Kenalog®, pub. 02/02/2011) herein referenced NCI.
Ishikawa discloses a self-magnetic (i.e., self-assembled) metal-salen complex compound, a local anesthetic containing this metal-salen complex compound, and an antineoplastic drug containing this metal-salen complex compound (abstract). A metal atom part in each of two molecules of a metal-salen complex or a derivative of the metal-salen complex is dimerized via water, and the metal-salen complex is mixed with a base to produce an ointment (abstract). As evidenced by Herchel which cited by Ishikawa, in the N,N’-ethylenbis(salicylaldimato) dianion, salen serves as the ligand (pg. 9870, Introduction).
Regarding triamcinolone acetonide, Ishikawa discloses Kenalog® as an ointment base (col. 4, line 28; col. 49, lines 10, 25-35; Fig. 16; claim 6). As evidenced by NCI, Kenalog® is a US brand name for triamcinolone acetonide (see third brand name listed on pg. 1 of document). Ishikawa demonstrates that by mixing the metal-salen complex compound, i.e., Formula (III) wherein M is Fe, with Kenalog® achieves an ointment that is more suited as an anti-tumor agent (col. 49, line 36; Example 8; Figs. 16 and 17; claims 1 and 6). Here the prior art anticipates the triamcinolone acetonide supported in the self-assembled iron complex limitation of the claims.
Ishikawa explains that a topical anesthetic is introduced in which side chains for giving positive or negative spin charge density are bonded to a basic skeleton of an organic compound, and which has suitability as a whole insofar as the topical anesthetic is guided, by means of magnetism by an external magnetic field; and if the topical anesthetic is applied to a human body or an animal, it is retained in an area where a magnetic field is applied topically by the magnetic field outside the body and the medicinal effects that the topical anesthetic originally has are exerted on the area (col. 3, lines 1-10). Ishikawa discloses that in Formulas (II) and (III) where the M is Fe; and wherein each of the a - I and Y is independently hydrogen or (i) to (vi); specifically in the case of (v): R3, wherein the R3 is a therapeutic drug bound to the self-magnetic metal-salen complex compound via spin charge transfer (col. 50, lines 53-55, claim 1).
Regarding π-π interaction and hydrogen bonding between the ligands limitation, Applicants’ description of the aromatic ring of the adenine moiety forms a π-π interaction in the specification (pg. 7, line 22, Fig. 1). While Ishikawa meets the limitation of the claim to require at least one ligand in line 4 of claim 1, the “hydrogen bonding between the ligands” does not apply. Nevertheless, as Ishikawa shows a coordination bond between salen and iron (col. 40, Formula (VI)), and as salen ligand contains aromatic ring(s), such π-π interaction is present.
Regarding claims 4-5, 16 and 19-20, these claims recite certain properties of the composition. MPEP § 2112.01 states that if a composition is physically the same, it must have the same properties. Since the complex taught by Ishikawa meet the structural limitations of the claims, the complex must have the same properties including with respect to the release time and self-disassembly time requirements of the claims. Notably Ishikawa discloses 0.01 wt% to 10 wt% of the self-magnetic metal-salen complex compound is mixed with Kenalog® (claims 5 and 6). Kenalog® is at concentrations of 100 mmol and 200 mmol; results of the Kenalog® and Fe salen complex compound over time (0-300 seconds) are provided (col. 49, lines 11-12, 21; see Fig. 16).
Specifically regarding claim 17 (i.e., accelerated, non-accelerated conditions), the properties recited are properties inherent to any iron complex. A working example of this is evidenced by Herchel where an exponential correlation was found between the magnetic properties and the electronic properties of the bridging ligand (basicity Kb) (pg. 9877, Conclusions). One skilled in the art would immediately recognize that this basicity influences the strength and nature of the bonds to the multiple metal centers.
Specifically regarding claim 18, Ishikawa teaches an AC magnetic field applied in which Kenalog is used as a base and mixed with the Fe salen complex compound (Fe salen complex compound; 9.25 mmol) increases the drug temperature by 2 degrees Celsius to 10 degrees Celsius and suggests that corresponds to a temperature range is a temperature zone capable of killing cancer cells in the living body during administration (col. 43, lines 44-59). As such, considering the broadest interpretation of the claim, Ishikawa meets the acceleration of disassembly as the conditions are applied (i.e., magnetic field).
It would have been prima facie obvious for a person of ordinary skill in the art ahead of the effective filing date of the claimed invention to utilize the teachings of Ishikawa with expected results. One would be motivated to do so because Ishikawa overcomes challenges surrounding binding strength and affinity between carrier and drug molecules by focusing on the positive or negative spin charge density on side chains to improve transfer to the affected site and effectiveness while achieving excellent noninvasiveness (col. 3, lines 3-11; col. 4, lines 4-5), to deliver a significant contribution to the art, absent evidence to the contrary. Temperature over time studies to substantiate the suitability of the Fe salen complex compound as an anti-tumor agent (col. 50, line 9). Ishikawa shows changes in weigh and results of differential thermal analysis with respect to metal-salen complex compounds (Fig. 1); specifically the Fe salen complex compound effects on melanoma growth in mice (col. 42, lines 55-65; Figs. 11-13). Further, Herchel provides evidence that suggests the N-donor ligands in the complex (i.e., [Fe(salen)(atz)]n) achieve favorable results with respect to cytotoxicity (abstract).
Claims 6, 8 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Ishikawa evidenced by Herchel and NCI as applied to claims 1, 4-5, 13 and 16-20 above, in view of Goucher (The Journal of Biological Chemistry, Vol. 239, No. 7, 2251-2255, July 1964).
The teachings of Ishikawa, Herchel and NCI above are incorporated herein.
While Ishikawa discloses that the Fe salen complexes may contain adenine and phosphate (col. 5, lines 45-52, see (4)) and that the “base” used to produce the ointment can include hydrophilic bases (col. 4, line 21), Ishikawa does not teach ATP.
Goucher teaches that ferric adenosine triphosphates such as Fe2ATP and Fe(ATP)2 are formed in solutions containing ferric iron and ATP where Fe3+ and ATP are of the same molarity (pg. 2251, col. 1, para. 2; col. 2, para. 3). For instance, compositions of ferric nucleotide phosphates with 1:1 complexes of iron and nucleotides are disclosed (pg. 2254, col. 2, para. 1). Goucher teaches that Fe-ATP is formed from ferric iron and FeATP by demonstrating the solubility of FeATP in solutions containing various concentrations of Fe3+ and ATP, that ferric iron forms a very stable complex with ATP and that different ligands achieve different stabilities (pg. 2254, col. 1-2, Fig. 1, Table IV). Thermodynamic activity of the compound is constant in FeATP saturated solutions (pg. 2253, col. 2, para. 4) further suggesting stability.
Regarding claim 6 (i.e., ATP, elected species) and claim 8 (i.e., ATP, hydrophilic), it would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to substitute one known salen of Ishikawa with the ATP of Goucher for a similar purpose of improving the drug delivery and the stability of the complex and actives. Simple substitution of one ligand for another is within the purview of the skilled artisan and would yield predictable results.
Regarding claim 14 (i.e., iron ion and the ligand; 5:1 to 1:1), Goucher prepared solutions of Fe3+ and ATP were of the same molarity (pg. 2251, col. 2, para. 3) and the ratio of iron to ATP is 1:1 (pg. 2254, col. 2, para. 1). Goucher teaches that the solubility of FeATP depends strongly on the ratio of total ATP to total iron, rather than on the absolute concentration of these reactants (pg. 2258, col. 1, para. 4).
Regarding claim 15 (i.e., ligand type, disassembly), Goucher teaches that ferric iron does form a very stable complex with ATP and other similar nucleotide phosphates (pg. 2254, bridging col. 1-2). Goucher teaches that formation constants (i.e., self-assembly) can be measured by the same method for the ferric compounds of inosine, guanosine, cytosine, and uridine triphosphates (pg. 2253, col. 1, para. 3). Here Goucher is teaching that different ligands will afford different stabilities of the complexes (pg. 2254, col. 2, para. 5, see Table IV). In addition the length of the phosphate chain may be an important influence in determining stability (pg. 2254, col. 2, para. 7).
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to apply the ratio and the ligand type teachings of Goucher to Ishikawa with expected results. One would be motivated to do so because Goucher suggesting a relationship between chain length and stability comports with Ishikawa’s studies to determine the electron transfer of a compound which binds with the metal-salen complexes by adding, modifying, and deleting side chains of each compound (col. 43, Example 7 - col. 44, line 12).
Response to Arguments
Applicants' arguments have been fully considered but they are not persuasive.
35 USC § 103
Applicants argue that Ishikawa, even evidenced by Herchel and NCI, fails to disclose or suggest at least the features as claim 1 recites in part, “a self-assembled complex containing an iron ion, consisting of: an iron ion; at least one ligand; and an active ingredient supported in the self-assembled complex, wherein the active ingredient is triamcinolone acetonide, and wherein the self-assembled complex comprises π-πinteraction and hydrogen bonding between the ligands," (Applicants’ emphasis) because Ishikawa fails to disclose or suggest every claimed feature (Remarks, pg. 9, section V.; pg. 10, para. 3).
The Examiner respectfully disagrees because Applicants’ description of the aromatic ring of the adenine moiety forms a π-π interaction in the specification (pg. 7, line 22, Fig. 1). While Ishikawa meets the limitation of the claim to require at least one ligand in line 4 of claim 1, the “hydrogen bonding between the ligands” does not apply. Nevertheless, as Ishikawa shows a coordination bond between salen and iron (col. 40, Formula (VI)), and as salen ligand contains aromatic ring(s), such π-π interaction is present.
For these reasons, Applicants' arguments are found unpersuasive.
Conclusion
All claims under consideration remain rejected; no claims are 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Karen Ketcham whose telephone number is (571)270-5896. The examiner can normally be reached 930-530 ET. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the Automated Interview Request at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at 571-272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Karen Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
Prosecution Insights