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 .
Information Disclosure Statement
The information disclosure statement filed on April 30, 2026 is acknowledged and has been considered by the examiner.
Drawings
The drawings are objected to for the following informalities:
Figure 2B provides two curves describing the absorption spectra of eNPS3 in its intact and disrupted forms. However, these curves are similar in appearance. From the provided key and the data, it is not clear which curve belongs to which sample. Therefore, it is difficult to interpret this figure.
Figures 12 and 19 are not readily interpretable in their current state. These figures are associated with a gradient color scale intended to communicate the intensity of a measured value from low to high. However, in the current form, the color scale keys indicate that dark colors correspond to both high and low intensity values. Thus, the examiner is unable to interpret the meaning of dark colored regions of the figures as presented.
Figure 12 contains the text “3hr” and “4hr” on the page, but it is not clear to what these labels refer.
Figure 18 provides survival plots. However, these curves are similar in appearance to each other. From the provided key and data, it is not clear which curve belongs to which experimental group. Therefore, it is difficult to interpret this figure.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
Both on page 11, lines 30-31 and page 16, line 29, the specification tells the reader to see supporting information. However, no such supporting information section is provided in the specification.
On page 21, line 11, there appears to be a formatting error for the metric prefix of the molarity unit describing the concentration of nanoparticles used in a method. This currently appears in the form of a box, which is not an understood character to modify the molarity unit. It appears this character should be µ, representing the micro metric prefix.
Appropriate correction is required.
Claim Objections
Claims 9 and 37 are objected to because of the following informalities:
Claim 9 recites “DPTA” when it appears to mean DTPA instead.
Claim 37 recites “claims 36.” Since this claim only refers to a singular claim, it should instead read as “claim 36.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-5, 8-10, 14-15, 17-21, 23-30, and 32-42 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “fatty acid” in claims 1, 4, 5, 8, 9, and 10 is used by the claim to mean “lipid” or “alkyl group” while the accepted meaning is “an acyclic aliphatic monocarboxylic acid.” The term is indefinite because the specification does not clearly redefine the term. The examples provided for such “chelator-fatty acid conjugates” are EDTA-hexadecylamide (Figure 1) and DTPA-hexadecylamide. These examples of chelator conjugates do not contain fatty acid groups. Using EDTA-hexadecylamide as an example, EDTA contains four carboxylic acid groups and a fatty acid within the accepted definition in the art would contain a carboxylic acid group. Upon reaction, a carboxylic acid group may change, such as the formation of an amide; though this often leaves the carbonyl from the carboxylic acid remaining in the final product. Thus, combination of EDTA with a carboxylic acid-containing fatty acid would likely result in a structure containing five carbonyl groups. However, the EDTA-hexadecylamide contains just four. Furthermore, the methods of preparing the “chelator-fatty acid conjugates” do not use fatty acids as a reagent and instead use hexadecylamine, which could instead be considered a lipid. Furthermore, “hexadecylamide” as recited in claim 8 is not a fatty acid, as it contains an amide and not a carboxylic acid group. This, too, could be considered a lipid. In view of the specification as a whole, it appears that the term “fatty acid” as used in the claims is instead meant to mean “lipid.” As the use of “fatty acid” in claims 1, 4, 5, 8, 9, and 10 is used in a way different from its accepted meaning in the art and the specification fails to clearly redefine the term, these claims are indefinite. Furthermore, claims 2, 3, 14-15, 17-21, 23-30, and 32-42 are rejected due to their dependency on these claims. For the purpose of examination, “fatty acid” will be interpreted in the context of the aforementioned conjugate to mean “lipid.”
Claim 1 recites that the porphyrin-phospholipid conjugate comprises one porphyrin, porphyrin derivative, or porphyrin analog… In this instance, the phrases “porphyrin derivative” and “porphyrin analog” render the claim indefinite. It is not clear what structure the porphyrin derivative or porphyrin analog has and how different the derivative may be from the parent porphyrin compound. Furthermore, claims 2-5, 8-10, 14-15, 17-21, 23-30, and 32-42 are rejected due to their dependency on claim 1.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance:
Claim 5 recites the broad recitation “12 to 22 carbons,” and the claim also recites “14 to 18 carbons” and “16 carbons” which are narrower statements of the range/limitation.
Claim 10 recites the broad recitation “15%-60%,” and the claim also recites “25%-50%,” 30%-40%,” and “about 30%” which are narrower statements of the range/limitation.
Claim 15 recites the broad limitation “20-40 molar %,” and the claim also recites “about 27 molar %” which is the narrower statement of the range/limitation.
Claim 30 recites the broad limitation “1-10 molar %,” and the claim also recites “2-7 molar %” which is the narrower statement of the range/limitation.
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Additionally, while claim 8 depends from claim 5, it is not rejected for said dependence as the hexadecylamide limitation of claim 8 overcomes the indefinite scope of carbon number in claim 5.
Claim 10 provides a limitation regarding the relative amount of chelator-fatty acid in the bilayer nanovesicle of claim 1. Claim 10 provides the measure of the relative amount as a percentage. However, a percentage is a relative value of one measurement to another. In order to compare values to determine a percentage, the identity of what value is to be measured must be defined. In this case, the percent composition is not clearly defined in terms of what value is to be compared between the chelator-fatty acid conjugate and the other components of the nanovesicle, making the scope of the claim indefinite. It is not clear whether this percentage relates to mass, volume, moles, etc. of the components of the vesicle. For the purpose of examination, the examiner will interpret this percentage to be a molar percentage of the chelator-fatty acid to the other components of the nanovesicle (mol/mol%).
Claim 24 requires the porphyrin-phospholipid conjugate to be “pyro-lipid.” To the examiner’s best understanding, this is not a term of the art with a definition a person of ordinary skill in the art would know. Furthermore, the specification does not define what is meant by this phrase. Thus, it is unclear what molecular structure is required to meet this limitation. Therefore, the claim is indefinite.
Claim 28 requires the molecular weight of the PEGylated emulsifier to be from about 1000 to 5000. However, no unit is provided for this molecular weight. Therefore, the claim is indefinite. Furthermore, claim 29 is rejected due to its dependence on claim 28. For the purpose of examination, the examiner will interpret the unit of the molecular weight to be in Daltons (which is equivalent to g/mol).
Claim 33 requires “the remaining composition of the bilayer nanovesicle substantially comprises the cholesterol.” It is not clear what is meant by the phrase “remaining composition.” The term “remaining” implies that the vesicle already comprises components other than cholesterol. Indeed, claim 1 requires a chelator-fatty acid conjugate and a porphyrin-phospholipid conjugate. However, claim 1 uses “comprising” language, allowing for the inclusion of other materials. Thus, it is not clear to what the term “remaining” in claim 33 is relative. Therefore, this limitation is indefinite. Furthermore, in the same limitation, the phrase “substantially comprises” is recited. In the context of this claim, it is unclear what “substantially comprises” means relative to “remaining composition.” It is not clear what percentage of the remaining composition must be cholesterol to read on the scope of the claim. Therefore, this terminology renders the claim indefinite. For the purpose of examination, the examiner will interpret this limitation to mean that cholesterol accounts for 50 molar % or more of the fraction of the vesicle composition that is neither the chelator-fatty acid conjugate nor the porphyrin-phospholipid conjugate.
Claim Rejections - 35 USC § 112(d)
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 2 and 25 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 2 includes glycinate among the options for what the aminopolycarboxylic acid is. However, to the examiner’s understanding, glycinate is a structure in which there is one amine and one carboxylic acid. Therefore, glycinate is not a compound that could be described as an aminopolycarboxylic acid, as is required in claim 1 (from which claim 2 depends). Thus, claim 2 fails to include all the limitations of the claim upon which it depends.
Claim 25 includes aza-boron dipyrromethene-phospholipid conjugates among options for what the porphyrin-phospholipid conjugate is. However, to the examiner’s understanding, aza-boron dipyrromethene dyes do not belong to the family of porphyrins, porphyrin derivatives, or porphyrin analogs. Therefore, the aza-boron dipyrromethene-phospholipid conjugate is not a molecule that could be described as a porphyrin-phospholipid conjugate wherein the conjugate comprises one porphyrin, porphyrin derivative, or porphyrin analog, as is required in claim 1 (from which claim 25 depends). Thus, claim 25 fails to include all the limitations of the claim upon which it depends.
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.
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.
Claims 1-5, 8-10, 14-15, 17-21, 23-30, and 32-42 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (US 9,072,774 B2) in view of Mulas (Mulas, G.; et al., ACS Appl. Bio Mater., 2020), Takeshita (Takeshita, T.; et al., J. Am. Oil Chem. Soc., 1982), and Liang (Liang, X.; et al., Biomaterials, 2014).
Zheng teaches bilayer nanovesicles comprising a porphyrin-phospholipid conjugate (Abstract). Zheng teaches that this porphyrin-phospholipid conjugate can be prepared by conjugating 1-Palmitoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine and Pyropheophorbide-a acid or Bacteriopheophorbide acid with the conjugation occurring at the sn-2 position of the phospholipid (Figure 1; Figure 2; and column 7, lines 28-31). Zheng also teaches that the porphyrin-phospholipid conjugate may comprise a metal chelated therein, including radioisotopes of a metal (column 7, lines 50-52). Zheng teaches that the nanovesicle comprises 15-100% porphyrin-phospholipid conjugate (column 6, lines 58-67). Zheng also teaches that the nanovesicle may further comprise PEG or PEG-lipid, including PEG-DSPE at about 5 molar % (column 7, lines 42-45) and/or cholesterol, preferably between 30-50 molar % (column 8, lines 32-34). Zheng teaches that the bilayer nanovesicle is substantially spherical, possessing a diameter between about 30 nm and about 200 nm (column 7, lines 46-49). Zheng also teaches methods of using the bilayer nanovesicle for photodynamic therapy (column 8, lines 57-64) and imaging a target area of a subject (column 9, lines 6-13).
Zheng does not teach bilayer nanovesicles containing a chelator-fatty acid conjugate wherein the chelator-fatty acid conjugate comprises an aminopolycarboxylic acid conjugated to a single chain fatty acid.
Mulas teaches lipid nanovesicles comprising manganese complexed to alkyl-modified chelators and the magnetic resonance properties of said nanovesicles (pg. 2401 Abstract). Mulas teaches incorporating EDTA modified with two C12-alkyl groups (HCDTA) or 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid (DO2A) modified with either two C12-alkyl (DD-DO2A) or two C16-alkyl groups (DH-DO2A) in liposomes (pg. 2402, Scheme 1; pg. 2402-2403, Liposome Preparation). The nanovesicles also contain DSPE-PEG-2000. These alkyl-modified aminopolycarboxylic acid chelating groups are bound to manganese (pg. 2402, Synthesis of the Metal Complexes). Mulas found that the alkyl group modifications of the chelating groups enabled incorporation of the metal complexes in the lipid bilayer of lipid nanovesicles (pg. 2403, left column, fourth paragraph). Nanovesicles comprising 20 molar % Mn(HCDTA) were found to have the highest relaxivity values at 0.5 T, 1.0 T, and 1.5 T at 298 K of all tested nanovesicles (pg. 2406, Figure 3). Mulas teaches that such nanovesicles could be developed as MRI contrast agents (pg. 2407, Conclusions).
Takeshita teaches conjugates of long-chain alkyl-amines and EDTA (pg. 104, Abstract). Takeshita teaches conjugates of EDTA and amines with C10, C12, C14, C16, and C18 alkyl groups to form amide bonds at the conjugation point (pg. 104, Fig. 1; and pg. 105, EDTA-monoalkylamides). Takeshita also teaches chelating several metals to these alkyl-modified EDTA conjugates (pg. 105, Metal chelates of EDTA-monoalkylamides; and pg. 105, Table II). Takeshita teaches that these amide EDTA conjugates have better water solubility than EDTA-monoalkyl esters and that they can form micelles (pg. 106, Surface and Interfacial Tensions). Takeshita also teaches that the metal-chelated EDTA-monoalkylamides have good emulsifying properties (pg. 107, Table V and Emulsifying Power).
Liang teaches nanoparticles comprising porphyrin-lipid conjugates for magnetic resonance imaging guided photodynamic therapy (pg. 6379, Abstract). These nanoparticles comprise porphyrin-conjugated lipids for photodynamic therapy and are further conjugated with metal-chelating porphyrin molecules to impart MRI contrast properties (pg. 6380, Fig. 1 and left column, second paragraph). The metal bound to the chelating porphyrin is manganese (pg. 6380, Section 2.2). Liang teaches that these nanoparticles possess both photodynamic therapy efficacy and MRI contrast agent properties (pg. 6386, Fig. 7; and pg. 6385, Fig. 6). Liang teaches that the Mn-chelate-enabled MRI imaging allowed for precise delivery of laser light to improve the efficiency of photodynamic therapy, reducing damage to surrounding healthy tissues (pg. 6386-6387, Conclusions).
A person of ordinary skill in the art would have recognized that each of Zheng, Mulas, and Liang teach lipid nanoparticles for pharmacological applications. It would be recognized that Liang provides a teaching, suggestion, or motivation to combine a porphyrin-lipid conjugate and a lipid-bound metal chelate as the porphyrin-lipid conjugate enables photodynamic therapy and the metal chelate enables MRI-guidance to improve the safety and efficiency of the photodynamic therapy (MPEP § 2143(I)(G)). Thus, the modification of the porphyrin-lipid conjugate bilayer nanovesicle with alkyl-modified aminopolycarboxylic acid metal chelates taught by Mulas would predictably result in a nanoparticle possessing both photodynamic therapy and MRI contrast properties, enabling more targeted therapy. Furthermore, a person of ordinary skill in the art would have recognized that both Mulas and Takeshita teach alkyl group modified EDTA conjugates and their metal chelate forms. It would be recognized that the differences in alkyl modification do not prevent the EDTA group from chelating metals. Thus, it would be recognized that the monoalkylamides of Takeshita could be substituted in the nanovesicles of Mulas (or the combination of Mulas and Zheng), as the molecules serve the same purpose and possess similar properties and structures (MPEP § 2143(I)(B)).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the porphyrin-phospholipid conjugate containing bilayer nanovesicle of Zheng with an alkyl-modified EDTA chelating group bound to manganese, as taught by Mulas, because this would enable MRI-guided photodynamic therapy, which improves treatment efficiency and limits undesired tissue damage, as taught by Liang. Furthermore, it would have been obvious to substitute the HCDTA of Mulas for the EDTA-monohexadecylamide of Takeshita, as both are alkylated EDTA chelators that can serve the same purpose of binding manganese. This would result in the predictable result of a multifunctional bilayer nanovesicle capable of MRI-guided photodynamic therapy comprising a porphyrin-phospholipid conjugate and a chelator-lipid conjugate.
Regarding claim 1, Zheng teaches a bilayer nanovesicle comprising a porphyrin-phospholipid conjugate wherein the porphyrin-phospholipid conjugate comprises one porphyrin, porphyrin derivative, or porphyrin analog covalently attached to a lipid side chain at the sn-1 or sn-2 position of one phospholipid (column 2, lines 19-25). Additionally, Takeshita teaches a conjugate of EDTA (an aminopolycarboxylic acid chelator) and hexadecylamine to form EDTA-monohexadecylamide, which is a chelator-lipid conjugate (which reads on “chelator-fatty acid conjugate,” see claim interpretation associated with 112(b) rejection) (pg. 104, Fig. 1 and pg. 105, Table 1). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 1 obvious.
Regarding claims 2 and 3, the aminopolycarboxylic acid chelator of Takeshita is EDTA (pg. 104, Fig. 1). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claims 2 and 3 obvious.
Regarding claims 4 and 5, Takeshita teaches EDTA-monoalkylamide conjugates with alkyl chains of 10-18 carbons, including 16 carbons (pg. 104, Fig. 1; pg. 105, Table 1; and pg. 105, EDTA-monoalkylamides). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claims 4 and 5 obvious.
Regarding claims 8 and 9, Takeshita teaches reacting EDTA with hexadecylamine to form EDTA-monohexadecylamide (which reads on EDTA-hexadecylamide) (pg. 105, EDTA-monoalkylamides). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claims 8 and 9 obvious.
Regarding claim 10, Mulas teaches bilayer nanovesicles comprising 10 molar % and 20 molar % alkyl modified EDTA (pg. 2402-2403, Liposome Preparation). Mulas also teaches that the MRI detection limit of the 20% metal complex particles is expected to be lower than those of the 10% formulation (pg. 2407), suggesting compositions with greater than 20% metal complex may have further improved MRI sensitivity. The disclosed 20 molar % composition falls within the claimed range of 15-60%, rendering the claimed range obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 10 obvious.
Regarding claims 14 and 15, Zheng teaches bilayer nanovesicles comprising at least 15 molar % porphyrin-phospholipid conjugate (column 2, lines 19-25). This is interpreted as a range of 15-100 molar %. Therefore, the claimed ranges fall within the range taught by the prior art, rendering them obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claims 14 and 15 obvious.
Regarding claims 17 and 18, Zheng teaches that the porphyrin, porphyrin derivative, and porphyrin analog may be hematoporphyrins, protoporphyrins, tetraphenylporphyrins, pyropheophorbides, bacteriochlorophylls, chlorophyll a, benzoporphyrin derivatives, tetrahydroxyphenyl chlorins, purpurins, benzochlorins, naphthochlorins, verdin, rhodins, keto chlorins, azachlorins, bacteriochlorins, tolyporphyrins, benzobacteriochlorins, expanded porphyrins, and porphyrin isomers (column 7, lines 1-14). Zheng also teaches that the expanded porphyrin may be a texaphyrin, a sapphyrin, or a hexaphyrin and the porphyrin isomer may be a porphycene, inverted porphyrin, or a naphthalocyanine (column 7, lines 15-18). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claims 17 and 18 obvious.
Regarding claim 19, Zheng teaches that the phospholipid in the porphyrin-phospholipid conjugate may comprise phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol (column 7, lines 22-25). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 19 obvious.
Regarding claim 20, Zheng teaches that the acyl side chain of the phospholipid may be 12 to 22 carbons long (column 7, lines 26-27). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 20 obvious.
Regarding claim 21, Zheng teaches that the porphyrin in the porphyrin-phospholipid conjugate may be pyropheophorbide-a acid or a bacteriochlorophyll derivative (column 7, lines 28-31). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 21 obvious.
Regarding claim 23, Zheng teaches that the phospholipid in the porphyrin-phospholipid conjugate may be 1-Palmitoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine (column 7, lines 32-34). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 23 obvious.
Regarding claim 24, Zheng teaches that the porphyrin-phospholipid conjugate may be pyro-lipid (column 7, lines 35-36). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 24 obvious.
Regarding claim 25, Zheng teaches that the porphyrin-phospholipid conjugate may be oxy-bacteriobhloriphyll-lipid (column 7, lines 37-38). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 25 obvious.
Regarding claim 26, Zheng teaches that the porphyrin can be conjugated to the glycerol group on the phospholipid by a carbon chain linker of 0 to 20 carbons (column 7, lines 39-41). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 26 obvious.
Regarding claims 27-29, Zheng teaches that the bilayer nanovesicle may further comprise PEG, PEG-lipid, or PEG-DSPE (column 7, lines 42-45). PEG-DSPE is a PEGylated emulsifier. Furthermore, Mulas teaches bilayer nanovesicles comprising alky-modified EDTA further comprising DSPE-PEG2000 (pg. 2402-2403, Liposome preparation). DSPE-PEG2000 is understood by the examiner to be the same as PEG-DSPE and to be in a form in with the molecular weight of the PEG portion of the molecule being 2000 Da, making the molecular weight of the full structure between 1000 and 5000 Da. This molecular weight value falls within the range of claim 28, rendering the range obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claims 27-29 obvious.
Regarding claim 30, Zheng teaches that the PEG-DSPE is present at an amount of about 5 molar % in the bilayer nanovesicle (column 7, lines 42-45). Furthermore, Mulas teaches nanoparticles comprising 5 molar % DSPE-PEG2000 (pg. 2402-2403, Liposome Preparation). These values fall within the claimed range. Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 30 obvious.
Regarding claim 32, Zheng teaches that the bilayer nanovesicle may further comprise cholesterol (column 8, lines 32-34). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 32 obvious.
Regarding claim 33, Zheng teaches the bilayer nanovesicle comprises at least 15 molar % (15-100%) porphyrin-phospholipid conjugate (column 6, lines 58-67). Additionally, Mulas teaches bilayer nanovesicles comprising 20 molar % alkyl group modified EDTA (pg. 2402-2403, Liposome Preparation). Furthermore, Zheng teaches that cholesterol may be present at 30-50 molar % in the bilayer nanovesicle (column 8, lines 32-34). In the combined embodiment described above wherein the EDTA-monohexadecylamide of Takeshita is present in the nanovesicle of Zheng at 20 molar % (taught by Mulas), at the minimum molar concentration of porphyrin-phospholipid conjugate in the scope of Zheng (15%), a total of 35 molar % of the bilayer nanovesicle is either porphyrin-phospholipid conjugate or chelator-lipid conjugate. In most embodiments, this percentage is higher, as Zheng allows for much higher concentrations of porphyrin-phospholipid conjugate. However, at this minimum value, the amount of molar % remaining is 65%. Thus, the teaching of cholesterol being added at 32.5 molar % or greater (with a maximum value of 65%) reads on the limitation of “remaining composition of the bilayer nanovesicle substantially comprises the cholesterol” (see claim interpretation in related 112(b) rejection). The 30-50 molar % range that Zheng teaches significantly overlaps with this range, rendering it obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 33 obvious.
Regarding claim 34, Zheng teaches that the cholesterol may be present at 30-50 molar % in the bilayer nanovesicle (column 8, lines 32-34). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 34 obvious.
Regarding claims 35-37, Zheng teaches that the bilayer nanovesicle is substantially spherical and is preferably about 100 nm in diameter. The value of about 100 nm is within the claimed ranges, rendering them obvious. Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claims 35-37 obvious.
Regarding claim 38, Zheng teaches that the porphyrin-phospholipid conjugate may further comprise a metal chelated therein, which may be a radioisotope of a metal (column 7, lines 50-52). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 38 obvious.
Regarding claim 39, Zheng teaches a method of making the bilayer nanovesicle in which the preparing occurs in a buffer (column 8, lines 35-44). This would result in a product in which the bilayer nanovesicle is present in a buffer. Additionally, Mulas describes preparing alkyl group modified EDTA containing bilayer nanovesicles in a HEPES buffer and describes that the final product was in a solution dialyzed against the HEPES buffer (pg. 2402-2403, Liposome Preparation). The examiner interprets this to describe the nanovesicle being present in a buffer solution. Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 39 obvious.
Regarding claim 40, as described above, the combination of Zheng, Mulas, Takeshita, and Liang teach the composition of claim 1. Furthermore, Zheng teaches a method of performing photodynamic therapy on a target area in a subject comprising administering the nanovesicle and irradiating the nanovesicle at the target area with a wavelength of light wherein the wavelength of light activates the porphyrin-phospholipid conjugate to generate singlet oxygen (column 8, lines 57-64). The examiner interprets step “a,” providing the composition of claim 1, to mean that the composition of claim 1 is obtained by any means. In order to administer the nanovesicle, it must be obtained and is therefore considered to be provided, reading on claimed step “a.” Additionally the “activates” in Zheng reads on the claimed language of “excites,” as both describe light being absorbed by the molecule to have the desired effect. Furthermore, singlet oxygen is a reactive oxygen species. Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 40 obvious.
Regarding claim 41, as described above, the combination of Zheng, Mulas, Takeshita, and Liang teach the composition of claim 1. Furthermore, Zheng teaches a method of imaging a target area in a subject comprising administering the nanovesicle and measuring and/or detecting photoacoustic signal at the target area (column 9, lines 6-13). The examiner interprets step “a,” providing the composition of claim 1, to mean that the composition of claim 1 is obtained by any means. In order to administer the nanovesicle, it must be obtained and is therefore considered to be provided, reading on claimed step “a.” Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 41 obvious.
Regarding claim 42, the method of making the porphyrin-phospholipid conjugate taught by Zheng states that preferably, the porphyrin-phospholipid conjugate comprises a metal chelated therein (column 8, lines 35-46). Zheng also teaches that metals chelated in the porphyrin may be radioisotopes of a metal (column 7, lines 50-52). Since the porphyrin-phospholipid conjugate of Zheng may preferably contain a chelated metal, which may be a radioisotope, the aforementioned methods of performing photodynamic therapy or imaging a subject (column 8, lines 57-64; and column 9, lines 6-18) may involve administering the radioisotope-chelated form of the nanovesicle. These methods require administering the composition to a subject. Furthermore, in order for the nanovesicle to be administered, it must have been obtained. Additionally, Zheng teaches that the porphyrins described can be formed with a metal chelated bilayer, providing an avenue for targeted metal delivery (column 17, lines 15-17). Therefore, the combined teachings of Zheng, Mulas, Takeshita, and Liang render claim 42 obvious.
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 1-5, 8-10, 14-15, 17-21, 23, 25-30, and 32-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 9,072,774 in view of Mulas (Mulas, G.; et al., ACS Appl. Bio Mater., 2020), Takeshita (Takeshita, T.; et al., J. Am. Oil Chem. Soc., 1982), and Liang (Liang, X.; et al., Biomaterials, 2014).
The claims of U.S. Patent No. 9,072,774 (henceforth referred to as the ‘774 patent) are drawn to a bilayer nanovesicles comprising a porphyrin-phospholipid conjugate. This porphyrin-phospholipid conjugate can be prepared by conjugating 1-Palmitoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine and Pyropheophorbide-a acid or Bacteriopheophorbide acid with the conjugation occurring at the sn-2 position of the phospholipid. The porphyrin-phospholipid conjugate may comprise a metal chelated therein. The nanovesicle comprises 35-100% porphyrin-phospholipid conjugate. The nanovesicle may further comprise PEG or PEG-lipid, including PEG-DSPE and/or cholesterol, preferably between 30-50 molar %. The bilayer nanovesicle is substantially spherical, possessing a diameter between about 30 nm and about 200 nm. The claims of the ‘774 patent are also drawn to methods of using the bilayer nanovesicle for photodynamic therapy and imaging a target area of a subject.
The claimed bilayer nanovesicle of the ‘774 patent does not teach bilayer nanovesicles containing a chelator-fatty acid conjugate wherein the chelator-fatty acid conjugate comprises an aminopolycarboxylic acid conjugated to a single chain fatty acid.
As described above, Mulas teaches lipid nanovesicles comprising manganese complexed to alkyl-modified chelators and the magnetic resonance properties of said nanovesicles (pg. 2401 Abstract). Mulas teaches incorporating EDTA modified with two C12-alkyl groups (HCDTA) or 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid (DO2A) modified with either two C12-alkyl (DD-DO2A) or two C16-alkyl groups (DH-DO2A) in liposomes (pg. 2402, Scheme 1; pg. 2402-2403, Liposome Preparation). The nanovesicles also contain DSPE-PEG-2000. These alkyl-modified aminopolycarboxylic acid chelating groups are bound to manganese (pg. 2402, Synthesis of the Metal Complexes). Mulas found that the alkyl group modifications of the chelating groups enabled incorporation of the metal complexes in the lipid bilayer of lipid nanovesicles (pg. 2403, left column, fourth paragraph). Nanovesicles comprising 20 molar % Mn(HCDTA) were found to have the highest relaxivity values at 0.5 T, 1.0 T, and 1.5 T at 298 K of all tested nanovesicles (pg. 2406, Figure 3). Mulas teaches that such nanovesicles could be developed as MRI contrast agents (pg. 2407, Conclusions).
As described above, Takeshita teaches conjugates of long-chain alkyl-amines and EDTA (pg. 104, Abstract). Takeshita teaches conjugates of EDTA and amines with C10, C12, C14, C16, and C18 alkyl groups to form amide bonds at the conjugation point (pg. 104, Fig. 1; and pg. 105, EDTA-monoalkylamides). Takeshita also teaches chelating several metals to these alkyl-modified EDTA conjugates (pg. 105, Metal chelates of EDTA-monoalkylamides; and pg. 105, Table II). Takeshita teaches that these amide EDTA conjugates have better water solubility than EDTA-monoalkyl esters and that they can form micelles (pg. 106, Surface and Interfacial Tensions). Takeshita also teaches that the metal-chelated EDTA-monoalkylamides have good emulsifying properties (pg. 107, Table V and Emulsifying Power).
As described above, Liang teaches nanoparticles comprising porphyrin-lipid conjugates for magnetic resonance imaging guided photodynamic therapy (pg. 6379, Abstract). These nanoparticles comprise porphyrin-conjugated lipids for photodynamic therapy and are further conjugated with metal-chelating porphyrin molecules to impart MRI contrast properties (pg. 6380, Fig. 1 and left column, second paragraph). The metal bound to the chelating porphyrin is manganese (pg. 6380, Section 2.2). Liang teaches that these nanoparticles possess both photodynamic therapy efficacy and MRI contrast agent properties (pg. 6386, Fig. 7; and pg. 6385, Fig. 6). Liang teaches that the Mn-chelate-enabled MRI imaging allowed for precise delivery of laser light to improve the efficiency of photodynamic therapy, reducing damage to surrounding healthy tissues (pg. 6386-6387, Conclusions).
A person of ordinary skill in the art would have recognized that each of the ‘774 patent, Mulas, and Liang teach lipid nanoparticles for pharmacological applications. It would be recognized that Liang provides a teaching, suggestion, or motivation to combine a porphyrin-lipid conjugate and a lipid-bound metal chelate as the porphyrin-lipid conjugate enables photodynamic therapy and the metal chelate enables MRI-guidance to improve the safety and efficiency of the photodynamic therapy (MPEP § 2143(I)(G)). Thus, the modification of the porphyrin-lipid conjugate bilayer nanovesicle with alkyl-modified aminopolycarboxylic acid metal chelates taught by Mulas would predictably result in a nanoparticle possessing both photodynamic therapy and MRI contrast properties, enabling more targeted therapy. Furthermore, a person of ordinary skill in the art would have recognized that both Mulas and Takeshita teach alkyl group modified EDTA conjugates and their metal chelate forms. It would be recognized that the differences in alkyl modification do not prevent the EDTA group from chelating metals. Thus, it would be recognized that the monoalkylamides of Takeshita could be substituted in the nanovesicles of Mulas (or the combination of Mulas and the ‘774 patent), as the molecules serve the same purpose and possess similar properties and structures (MPEP § 2143(I)(B)).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the porphyrin-phospholipid conjugate containing bilayer nanovesicle of the ‘774 patent with an alkyl-modified EDTA chelating group bound to manganese, as taught by Mulas, because this would enable MRI-guided photodynamic therapy, which improves treatment efficiency and limits undesired tissue damage, as taught by Liang. Furthermore, it would have been obvious to substitute the HCDTA group of Mulas for the EDTA-monohexadecylamide of Takeshita, as both are alkylated EDTA chelators that can serve the same purpose of binding manganese. This would result in the predictable result of a multifunctional bilayer nanovesicle capable of MRI-guided photodynamic therapy comprising a porphyrin-phospholipid conjugate and a chelator-lipid conjugate.
Regarding instant claim 1, conflicting claim 1 of the ‘774 patent teaches a bilayer nanovesicle comprising a porphyrin-phospholipid conjugate wherein the porphyrin-phospholipid conjugate comprises one porphyrin, porphyrin derivative, or porphyrin analog covalently attached to a lipid side chain at the sn-1 or sn-2 position of one phospholipid. Additionally, Takeshita teaches a conjugate of EDTA (an aminopolycarboxylic acid chelator) and hexadecylamine to form EDTA-monohexadecylamide, which is a chelator-lipid conjugate (which reads on “chelator-fatty acid conjugate,” see claim interpretation associated with 112(b) rejection) (pg. 104, Fig. 1 and pg. 105, Table 1).
Regarding instant claims 2 and 3, the aminopolycarboxylic acid chelator of Takeshita is EDTA (pg. 104, Fig. 1).
Regarding instant claims 4 and 5, Takeshita teaches EDTA-monoalkylamide conjugates with alkyl chains of 10-18 carbons, including 16 carbons (pg. 104, Fig. 1; pg. 105, Table 1; and pg. 105, EDTA-monoalkylamides).
Regarding instant claims 8 and 9, Takeshita teaches reacting EDTA with hexadecylamine to form EDTA-monohexadecylamide (which reads on EDTA-hexadecylamide) (pg. 105, EDTA-monoalkylamides).
Regarding instant claim 10, Mulas teaches bilayer nanovesicles comprising 10 molar % and 20 molar % alkyl modified EDTA (pg. 2402-2403, Liposome Preparation). Mulas also teaches that the MRI detection limit of the 20% metal complex particles is expected to be lower than those of the 10% formulation (pg. 2407), suggesting compositions with greater than 20% metal complex may have further improved MRI sensitivity. The disclosed 20 molar % composition falls within the claimed range of 15-60%, rendering the claimed range obvious (MPEP § 2144.05(I)).
Regarding instant claims 14 and 15, conflicting claims 1 and 2 of the ‘774 patent require the bilayer nanovesicles comprising at least 35 molar % porphyrin-phospholipid conjugate. This is interpreted as a range of 35-100 molar %. Therefore, the claimed ranges fall within the range taught by the prior art, rendering them obvious (MPEP § 2144.05(I)).
Regarding instant claim 17, conflicting claim 1 of the ‘774 patent requires the porphyrin, porphyrin derivative, or porphyrin analog be selected from the group consisting of hematoporphyrins, protoporphyrins, tetraphenylporphyrins, pyropheophorbides, bacteriochlorophylls, chlorophyll a, benzoporphyrin derivatives, tetrahydroxyphenyl chlorins, purpurins, benzochlorins, naphthochlorins, verdin, rhodins, keto chlorins, azachlorins, bacteriochlorins, tolyporphyrins, benzobacteriochlorins, expanded porphyrins, and porphyrin isomers.
Regarding instant claim 18, conflicting claim 3 of the ‘774 patent requires that the expanded porphyrin may be a texaphyrin, a sapphyrin, or a hexaphyrin and the porphyrin isomer may be a porphycene, inverted porphyrin, or a naphthalocyanine.
Regarding instant claim 19, conflicting claim 4 of the ‘774 patent requires that the phospholipid in the porphyrin-phospholipid conjugate may comprise phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol.
Regarding instant claim 20, conflicting claim 5 of the ‘774 patent requires that the acyl side chain of the phospholipid may be 12 to 22 carbons long.
Regarding instant claim 21, conflicting claim 6 of the ‘774 patent teaches that the porphyrin in the porphyrin-phospholipid conjugate may be pyropheophorbide-a acid and conflicting claim 7 teaches that the porphyrin may be a bacteriochlorophyll derivative.
Regarding instant claim 23, conflicting claim 8 of the ‘774 patent teaches that the phospholipid in the porphyrin-phospholipid conjugate may be 1-Palmitoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine.
Regarding instant claim 25, conflicting claim 9 of the ‘774 patent teaches that the porphyrin-phospholipid conjugate may be oxy-bacteriobhloriphyll-lipid.
Regarding instant claim 26, conflicting claim 10 of the ‘774 patent teaches that the porphyrin can be conjugated to the glycerol group on the phospholipid by a carbon chain linker of 0 to 20 carbons.
Regarding instant claims 27-29, conflicting claims 11-14 of the ‘774 patent are drawn to embodiments of the bilayer nanovesicle further comprising PEG, PEG-lipid, or PEG-DSPE. PEG-DSPE is a PEGylated emulsifier. Furthermore, Mulas teaches bilayer nanovesicles comprising alky-modified EDTA further comprising DSPE-PEG2000 (pg. 2402-2403, Liposome preparation). DSPE-PEG2000 is understood by the examiner to be the same as PEG-DSPE and to be in a form in with the molecular weight of the PEG portion of the molecule being 2000 Da, making the molecular weight of the full structure between 1000 and 5000 Da. This molecular weight value falls within the range of claim 28, rendering the range obvious (MPEP § 2144.05(I)).
Regarding instant claim 30, conflicting claim 12 of the ‘774 patent is drawn to an embodiment in which the PEG is present in an amount of about 5 molar %. Furthermore, Mulas teaches nanoparticles comprising 5 molar % DSPE-PEG2000 (pg. 2402-2403, Liposome Preparation). These values fall within the claimed range.
Regarding instant claim 32, conflicting claim 23 of the ‘774 patent is drawn to an embodiment in which the bilayer nanovesicle may further comprise cholesterol.
Regarding instant claim 33, conflicting claim 1 of the ‘774 patent requires the bilayer nanovesicle comprises at least 35 molar % (35-100%) porphyrin-phospholipid conjugate. Additionally, Mulas teaches bilayer nanovesicles comprising 20 molar % alkyl group modified EDTA (pg. 2402-2403, Liposome Preparation). Furthermore, conflicting claim 23 of the ‘774 patent teaches that cholesterol may be present at 30-50 molar % in the bilayer nanovesicle. In the combined embodiment described above wherein the EDTA-monohexadecylamide of Takeshita is present in the nanovesicle of the ‘774 patent at 20 molar % (taught by Mulas), at the minimum molar concentration of porphyrin-phospholipid conjugate in the scope of conflicting claim 1 of the ‘774 patent (35%), a total of 55 molar % of the bilayer nanovesicle is either porphyrin-phospholipid conjugate or chelator-lipid conjugate. In most embodiments, this percentage is higher, as conflicting claim 1 of the ‘774 patent allows for much higher concentrations of porphyrin-phospholipid conjugate. However, at this minimum value, the amount of molar % remaining is 45%. Thus, the teaching of cholesterol being added at 22.5 molar % or greater (with a maximum value of 45%) reads on the limitation of “remaining composition of the bilayer nanovesicle substantially comprises the cholesterol” (see claim interpretation in related 112(b) rejection). The 30-50 molar % range of conflicting claim 23 of the ‘774 patent significantly overlaps with this range, rendering it obvious (MPEP § 2144.05(I)).
Regarding instant claim 34, conflicting claim 23 of the ‘774 patent allows the cholesterol to be present at 30-50 molar % in the bilayer nanovesicle. This is within the instantly claimed range, rendering it obvious.
Regarding instant claims 35-37, conflicting claim 15 of the ‘774 patent is drawn to embodiments of the bilayer nanovesicle in which the nanovesicle is substantially spherical and between about 30 nm and about 200 nm in diameter. This range encompasses the instantly claimed ranges, rendering them obvious. Furthermore, conflicting claim 16 of the ‘774 patent is drawn to an embodiment wherein the nanovesicle is about 100 nm in diameter. This value is within the instantly claimed ranges, also rendering them obvious.
Regarding instant claim 38, conflicting claim 18 of the ‘774 patent is drawn to embodiments in which the porphyrin-phospholipid conjugate may further comprise a metal chelated therein, which may be a radioisotope of a metal.
Conclusion
All claims are rejected.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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