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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/3/2025 has been entered.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
35 U.S.C. 103
Applicant's arguments filed 6/13/2025 regarding rejections under 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant submits that 1) the combination of features (an injection rate 2-4mL/min; a temperature range of 50-80C; ethanol removal through evaporation; a dilution step, and a small, polycharged therapeutic molecule such as methotrexate or doxorubicin) are not obvious in view of Geldhof, Niyikiza, and Cavaco Paulo and 2) the method claims demonstrate unexpected results based upon their ability to achieve superior encapsulation efficiency and uniformity in fewer processing steps.
Regarding 1), first, it is noted that a defined injection rate is not recited in the instant claims. Thus, arguments pertaining to this limitation are moot.
Second, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Additionally, Applicants further submit that the combination of Cavaco Paulo with the remaining citations of record would require impermissible hindsight reconstruction in order to arrive at the method. Although applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971) (see MPEP 2145(X)(A)). With regards to the instant case, Cavaco Paulo may not teach method steps directly but does teach liposomes compositionally similar to those that the instant method claims would render. In considering the step whereby a targeting agent is incorporated into the liposome made, one skilled in the art would necessarily consider other pieces of art that describe compositionally similar liposomes, regardless of whether explicit method steps are taught. Moreover, as the instant specification indicates that the utility of generating such liposomes are to treat a variety of diseases, including cancer; thus, one skilled in the art would look to other liposomes designed to treat cancer, such as those taught by Cavaco Paulo.
Regarding 2), MPEP 716.02(b)(I) states that the burden is on the Applicant to establish that the results are unexpected and significant: “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).” In the instant application, none of the data put forth demonstrate statistical significance, including that in Tables 1 and 2, as cited in arguments. Thus, this requirement regarding unexpected results has not been met.
Additionally, the art of record similarly demonstrates similar rates of encapsulation efficiency and uniformity (monodispersity) with the same number of steps (see Geldhof, Pg 1, lines 38-41 and 31-32, respectively; rates of encapsulation also discussed in prior Office Action from 8/4/2025 in Response to Arguments section).
Consequently, the arguments set forth are insufficient to overcome the outstanding rejections under 35 U.S.C. 103, which have been maintained/modified herein.
Double Patenting
Applicants submit that US ‘320 is patently distinct from the instant claims as the claims of ‘320 are drawn to formulations and do not recite method steps. However, in view of the art of record, it would be obvious to generate or render the liposomes claimed in US ‘320 using the instantly claimed method steps. Therefore, the double patenting rejection has been maintained and modified herein.
Priority
The instant application is a 371 of PCT/IB2020/054346, which claims foreign priority to PT115500 with a filing date of 5/7/19. The priority date of 5/7/19 based on PT115500 is acknowledged.
Claim Status
Claims 1, 3, 7-10, 12-18, 20, and 22-23 are pending. Claims 2, 4-6, 11, 19, and 21 have been cancelled by the Applicant. Claim 1 is currently amended.
New - Claim Objections
Claim 1 is objected to because of the following informalities: the limitation that the injection should occur under agitation occurs twice (see lines 6 and 8). Appropriate correction is required.
New - Claim Interpretation
Claim 1 recites several limitations regarding the active ingredient, including that it is a small and polycharged molecule, an imaging or therapeutic agent, and methotrexate, doxorubicin, or a mixture thereof. The active ingredient of claim 1 is being interpreted as methotrexate or doxorubicin, which each of which possesses properties that make them small and polycharged molecules as well as therapeutic agents.
New - Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 7-10, 12-18, 20, and 22-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites that the resulting liposomal dispersion be diluted in “a further diluted aqueous phase”. This limitation makes the scope of this claim indefinite as it is unclear whether the further diluted aqueous phase is the same aqueous phase as that recited in line 5 or can be any aqueous phase.
Claim 1 additionally recites that the active ingredient is a small and polycharged molecule, is an imaging or therapeutic agent, and is methotrexate, doxorubicin, or mixtures thereof. The limitations that the active ingredient is “polycharged” and “an imaging agent” render the scope of the claim indefinite. Regarding the limitation “polycharged”, the instant specification states that both methotrexate and doxorubicin are polycharged at around pH 4 to around pH 7 (see instant [0018 and 0041]; also recited in claim 9); however, it is known in the art that doxorubicin can be singly charged at physiological pH, as evidenced by Liu et al. (Electrospun poly (L-lactic acid)/gelatine membranes loaded with doxorubicin for effective suppression of glioblastoma cell growth in vitro and in vivo. Regen Biomater. 2021 Jul 30;8(5):rbab043.; Pg 2, left column, third paragraph). As no pH is recited in the claim, it is unclear under what conditions/pH the liposome should be to maintain the polycharged nature of doxorubicin.
Regarding the “imaging agent” limitation, the instant specification does not define either methotrexate or doxorubicin as imaging agents, only therapeutic agents (see instant Tables III and IV).
Claim 1 additionally recites that the ethanolic/aqueous phase volume ratio is 1:1 and the ethanol has a concentration between 40-60% relative to initial aqueous volume. These limitations render the scope of the claim indefinite as it is unclear how a concentration of ethanol less than or greater than 50% could result in a 1:1 ethanolic/aqueous phase volume ratio.
Further, by virtue of their dependency on claim 1, claims 3, 7-10, 12-18, 20, and 22-23 are also hereby rejected for these same reasons.
For purposes of examination, the following interpretations will be used:
The limitation “a further diluted aqueous phase” is being interpreted to be the same or a different aqueous phase as that recited in line 5 of claim 1.
The limitation “an active ingredient” is being interpreted as methotrexate (elected species) or doxorubicin, which each of which possesses properties that make them small and polycharged molecules as well as therapeutic agents, as stated above in the claim interpretation section.
The limitations “the ethanolic/aqueous phase volume ratio is 1:1” and “the ethanol has a concentration between 40-60% relative to initial aqueous volume” are being interpreted as a 1:1 volume ratio and a 50% concentration.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 10, 14, 20, 22, and 23 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1, from which the above claims depend, recites that the active ingredient is a small and polycharged molecule, is an imaging or therapeutic agent, and is methotrexate, doxorubicin, or mixtures thereof.
Claim 10 recites the active ingredient is an anticancer drug, antirheumatic drug, anti-neurodegenerative diseases drug, antioxidant drug, anti-inflammatory drug, antipyretic drug, antibiotic drug, antiviral drug, analgesic drug or combinations thereof. Methotrexate and doxorubicin are an anticancer drugs, as described in [0061]/Table III of the instant specification. Thus, claim 10 does not further limit its parent claim 1. Moreover, claim 10 is further rejected because it recites that the active ingredient can be a variety of drugs that are mutually-exclusive with the anticancer nature of methotrexate and doxorubicin, i.e., methotrexate and doxorubicin are not antibiotics.
Claim 14 recites the ethanolic phase comprises anionic, neutral, or cationic phospholipids. Because phospholipids can only be one of the three types listed - anionic, neutral, or cationic - claim 14 does not further limit its parent claim 1.
Claim 20 recites the active ingredient is an imaging or therapeutic agent. As this limitation is recited in claim 1, claim 20 does not further limit.
Claim 22 recites the imaging agent is a dye. This claim does not incorporate all of the limitations of its parent claim 1 because claim 1 requires that the active ingredient be methotrexate or doxorubicin, neither of which is described as a dye in the instant specification.
Claim 23 recites the active ingredient is methotrexate, doxorubicin, or a mixture thereof. As this limitation is recited in claim 1, claim 23 does not further limit.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained/Modified - 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. 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 1, 3, 7-10, 12-18, 20, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable Niyikiza et al. (US2016/0228573 A1, published 8/11/16, cited on IDS filed 11/5/21), Geldhof et al. (WO2017/223135 A1, published 12/28/17, cited on IDS filed 11/5/21), and Cavaco Paulo (US9,393,320 B2, published 7/19/16).
Niyikiza teaches a liposomal antifolate composition comprising a medium comprising a liposome including an interior space; a bioactive antifolate agent (active ingredient) disposed within said interior space; a PEG attached to an exterior of the liposome; and a targeting moiety (targeting agent) comprising a protein with specific affinity for at least one folate receptor, said targeting moiety attached to at least one of the PEG and the exterior of the liposome ([0008]).
Niyikiza teaches that the liposomes may contain bioactive agents (active ingredients) that are anti-cancer (antineoplastic) agents ([0007]). In some embodiments, the liposomes may contain methotrexate as the bioactive agent (active ingredient [0016, 0098]).
Example 1 of Niyikiza describes a method of preparing liposomes and encapsulating active ingredient(s) in them. The lipid components of the liposome membrane are weighed out and combined as a concentrated solution in ethanol at a temperature of around 65°C; in this example, the lipids used are hydrogenated soy phosphatidyl choline, cholesterol, DSPE-PEG-2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]), PEG-DSPE-malemide and PEG-DSPE-FITC (mixing hydrophobic molecules of phospholipids and a steroid with ethanol). Pemetrexed (active ingredient) is dissolved in an aqueous buffer and heated to 65°C. The ethanolic lipid solution is injected into the Pemetrexed solution using a small-bore needle. During this step, the drug solution is well stirred using a magnetic stirrer. The mixing is performed at an elevated temperature (63-72°C) to ensure that the lipids are in the liquid crystalline state, as opposed to the gel state that they attain at temperatures below the lipid transition temperature Tm=51-54°C. As a result, the lipids are hydrated and form multiple bilayer (multilamellar) vesicles (MLV) containing pemetrexed in the aqueous core ([0152]).
Although Niyikiza does not explicitly teach evaporation of the ethanol after formation of the liposomes, one skilled in the art would recognize that by mixing and heating the ethanolic-aqueous solution post-injection would result in the evaporation of ethanol. Thus, Niyikiza implicitly teaches this step.
Niyikiza further indicates that extra-liposomal Pemetrexed is removed using dialysis or tangential flow filtration against a suitable buffer ([0155]).
Niyikiza does not explicitly teach that the ethanolic/aqueous phase volume ratio is 1:1 nor that the ethanol has a concentration between 40-60% relative to initial aqueous volume. Further, Niyikiza does not explicitly teach including the targeting agent in the aqueous phase nor a separate step wherein the liposomal dispersion is diluted 1-10-fold in a further diluted aqueous phase.
Geldhof teaches a method of producing lipid nanoparticles (liposomes; Pg 6, lines 1-9), including the steps of providing a lower alkanol solution (ethanol) including lipids, providing an aqueous solution (aqueous phase), and injecting the lower alkanol solution to the aqueous solution to produce lipid nanoparticles (Pg 1, lines 21-25).
Geldhof teaches that the term "lower alkanol" refers to an alcohol with 6 or fewer carbon atoms. Examples of lower alkanols include but are not limited to methanol, ethanol, propanol, pentanol, their isomers, and mixtures thereof (Pg 4, lines 17-19). The MPEP states that the selection of known materials based on their suitability for their intended uses is prima facie obvious. See MPEP § 2144.07. "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
Geldhof further teaches that the lipids can be phospholipids (Pg 12, lines 25-33). Geldhof notes that using phospholipids to make nanoparticles can produce limit size lipid nanoparticles that include a lipid bilayer surrounding an aqueous core or a hydrophobic core. The ability to generate an aqueous core or a hydrophobic core is advantageous in that it can accommodate a wider range of encapsulants depending on their solubility.
Geldhof teaches that in some embodiments the volume of the lower alkanol solution (ethanol) injected is between 10% and 100% of the volume of the aqueous solution (Pg 7, lines 16-20; a volume of 100% of the aqueous solution would necessarily result in a 1:1 volume ratio of the ethanolic to aqueous phase as well as constitute an ethanol concentration of 50% relative to the initial aqueous volume). Geldhof states that the greater the volume of the lower alkanol solution relative to the aqueous solution, the more concentrated the suspension of lipid nanoparticles will be upon completion of injection (Pg 7, lines 23-24). In some embodiments, the aqueous solution may be stationary or under mixing or agitation (Pg 7, lines 6-7).
Cavaco Paulo teaches liposomal formulations and methods of making (Title). Cavaco Paulo teaches that the inclusion of a targeting peptide that contains folic acid or an antibody of the folic acid receptor to liposomal formulations, which can improve liposomal targeting to specific cells, particularly cancer cells (Abstract; Col. 2, lines 4-26). In their methods of making, Cavaco Paulo introduces the targeting peptide into the aqueous phase, which comprises PBS (Col. 4, lines 20-24 and lines 34-38). Cavaco Paulo further notes that the addition of a reagent to the lipid solution vs. the aqueous solution depends on the properties of the reagent – in other words, whether the reagent is hydrophobic (add to the lipid solution) or hydrophilic (add to the aqueous solution; Col. 4 lines 24-39).
Thus, regarding claims 1, 3, 7, and 8, Niyikiza teaches a method of preparing liposomes and encapsulating active ingredients in them that consists of generating an ethanolic solution comprising phospholipids and cholesterol, injecting the ethanolic solution into an aqueous solution comprising an active ingredient, evaporating the ethanol, and removing excess active ingredient that is not encapsulated by tangential flow filtration. Geldhof teaches a method of making liposomes that consists of providing an aqueous solution, providing an ethanolic solution including lipids, and injecting it into the aqueous solution to produce nanoparticles that encapsulate therapeutics; moreover, Geldhof teaches the relative volumes of ethanol and aqueous phases to use in order to generate a more concentrated liposomal dispersion. Therefore, it would be prima facie obvious to use the ratios of Geldhof in the method taught by Niyikiza in order to generate a more concentrated dispersion of liposomes, which would allow for dilution of the dispersion to a desired concentration prior to downstream or subsequent applications. Practically, one skilled in the art would be motivated to use such a volumetric ratio in order to minimize the work required to accumulate a high amount of liposomes. One skilled in the art would have a reasonable expectation of success as Geldhof established the parameters needed to achieve a concentrated liposomal dispersion.
Further, Cavaco Paulo teaches adding a peptide targeting agent to an aqueous buffered solution in a method of making liposomes. Cavaco Paulo also teaches that the addition of a reagent to a lipidic vs. aqueous solution depends on the properties of said reagent. Therefore, it would be prima facie obvious incorporate the peptide targeting agent into the aqueous buffer, as taught by Cavaco Paulo. One skilled in the art would be motivated to do so because they would recognize that the physical and chemical properties of the target agent would determine which phase – ethanolic or aqueous – to incorporate it into. In the instant case, wherein the targeting agent is a peptide, one skilled in the art would want to add the targeting agent into the aqueous phase in order to maintain the its solubility and activity, as demonstrated by Cavaco Paulo. Moreover, one skilled in the art would have a reasonable expectation of success as Cavaco Paulo demonstrated that this approach – introducing the targeting agent into the aqueous buffer solution rather than the lipidic solution – facilitated the creation of liposomes with the desired targeting capacity, indicating preservation of the peptide targeting agent’s structure and functional activity.
Finally, Niyikiza, Geldhof, and Cavaco Paulo do not teach a step wherein the liposomal dispersion is diluted 1-10-fold in a further diluted aqueous phase. However, one skilled in the art would recognize that the concentration of the liposomal dispersion produced by the above method may not necessarily be the desired concentration and achieving the desired concentration would require dilution of the dispersion. In particular, Geldhof teaches administering liposomes formed from the method of making to individuals in need thereof (Formulations, starting Pg 32), which may require a certain concentration more dilute than what is produced. Moreover, as the method includes a step wherein the ethanol injected into the system is evaporated, meaning that the resulting liposomal dispersion exists in the aqueous phase/buffer, it would be obvious to dilute the dispersion in a further diluted aqueous phase.
Regarding claims 9, 10, and 23, Niyikiza teaches that the liposomes may contain bioactive agents (active ingredients) that are anti-cancer (antineoplastic) agents ([0007]). In some embodiments, the liposomes may contain methotrexate as the bioactive agent (active ingredient [0016, 0098]). The instant specification discloses that methotrexate is negatively charged at about pH 4-7 (see [0041]).
Regarding claim 12, Cavaco Paulo teaches several peptides covalently attached at their N-termini to folic acid (targeting agent) that can be used to target cells expressing folate receptors (Col. 4 lines 65-67 through Col. 5, lines 10-37). SEQ ID NO: 10 from Cavaco Paulo recites a peptide with an 11 amino acid sequence that has 91.7% local similarity to the instant SEQ ID NO: 1, which meets the claim limitation of a peptide having an amino acid sequence at least 90% identical to the instant SEQ ID NO: 1, as shown below:
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606
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Greyscale
Regarding claim 13, Geldhof also teaches that in some embodiments the aqueous solution further includes a buffer such as PBS (Pg 2, lines 11-13).
Regarding claim 14, Geldhof teaches that the lipids in the lower alkanol solution (ethanol) can be cationic lipids, anionic lipids, neutral lipids, or other lipids (Pg 8, lines 10-14).
Regarding claim 15, Geldhof teaches that in some instances, the phospholipids in the ethanolic phase can be 1,2-Dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE; Pg 13, lines 1-22).
Regarding claims 16-18, Geldhof teaches that in some embodiments, polyethylene glycol (PEG) is included as part of the lipid components in the lower alkanol solution (Pg 23 line 20 – Pg 24 line 11). PEG can be included in nanoparticles to enhance their delivery (stealth agent; Pg 24 line 39 – Pg 25 line 2). The instant specification teaches that PEG is a stealth agent (see [0045]). In some embodiments, PEG is a PEG-modified lipid (PEG bound to a phospholipid; Pg 14, line 1).
Regarding claims 20 and 22, Niyikiza also teaches that the liposomal compositions can contain detectable markers (imaging agent), which can include a dye ([0093]). In some instances, the detectable marker can be the dye fluorescein isothiocyanate (FITC; [0011], claim 8).
Maintained/Modified - Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 7-10, 12-18, 20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 8, 9, 10, 13, 14, 15, 16 and 18-20 of U.S. Patent No. 9,393,320 B2 (published 7/19/16) in view of Niyikiza et al. (US2016/0228573 A1, published 8/11/16, cited on IDS filed 11/5/21), Geldhof et al. (WO2017/223135 A1, published 12/28/17, cited on IDS filed 11/5/21), and Cavaco Paulo (US9,393,320 B2, published 7/19/16). Although the claims at issue are not identical, they are not patentably distinct from each other because they claim overlapping subject matter.
Claim 1 of US ‘320 is drawn to a preparation comprising liposomes wherein the liposomes comprise an intra-liposomal core and a liposomal membrane, one or more peptides each of which is 10-22 amino acids in length and has a sequence that is at least 95% homologous to a sequence selected from the group consisting of SEQ ID NO: 1-13, wherein the peptide comprises folic acid ligand or an antibody of a folic acid receptor and is bound at its N-terminus to the liposomal membrane; and a therapeutic or imaging agent. As shown above, the instant SEQ ID NO: 1 exhibits 91.7% local sequence identity to SEQ ID NO: 10 of US’ 320.
Claims 2, 3, 4, 6, 8, 10, and 11 of US patent ‘320 are drawn to further embodiments of the preparation described in claim 1, including phospholipids that are anionic, neutral, or cationic (claim 2); liposomes further comprised of a steroid, an agent of invisibility (stealth agent) or mixture thereof (claim 3); a steroid that is cholesterol (claim 4); the agent of invisibility (stealth agent) comprises polyethylene glycol (PEG) or a ganglioside (claim 6); the polyethylene glycol (PEG) is bound to a phospholipid (claim 8); the therapeutic or imaging agent is hydrophilic or hydrophobic (claim 10); and the therapeutic agent is a siRNA or a pharmaceutical compound (claim 11).
US ‘320 does not explicitly teach a method of producing the liposomes described above.
As referenced above, Niyikiza, Geldhof, and Cavaco Paulo teach a method of making liposomes comprising the steps of preparing an ethanolic phase with phospholipids and cholesterol, preparing an aqueous phase with an active ingredient such as methotrexate, and a targeting agent, such as a peptide, injecting a ratio 1:1 ethanolic phase into the aqueous phase under increased temperature and agitation, evaporating the ethanol, removing active ingredient that remains free by tangential flow filtration, and diluting the liposomal dispersion. It would be prima facie obvious to one of ordinary skill in the art to incorporate the teachings of Niyikiza, Geldhof, and Cavaco Paulo into US ‘320, thereby arriving at the instant invention. One skilled in the art would have a reasonable expectation of success as practicing these steps would render the liposomes claimed by US ‘320. Thus, the claims are obvious in view of US ‘320.
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658