DETAILED ACTION
Status of the Claims
Claims 1-20 are pending in the instant application and are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The U.S. effective filing date has been determined to be 06/13/2018, the filing date of the CN-201810607846.X.
Information Disclosure Statement
The information disclosure statements submitted on 10/09/2024 and 07/17/2025 were filed before the mailing date of the first office action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-4, 10, 12-14, and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description Rejection.
Scope of the Claimed Invention:
Applicant claims a method of treating tumors consisting of administering a therapeutically effective amount of a medicament containing black phosphorus nanosheet (instant claim 1). Applicant claims the black phosphorus nanosheet is subjected to surface modification for enhancing targeting efficiency and/or stability (claims 2 & 12); wherein the surface modification for enhancing stability is passive package modification based on liposomes or polymer molecules, ligand modification based on coordination bonding, and/or covalent modification (claims 3 & 13); wherein the surface modification for enhancing stability is a compound modification, a peptide modification, and/or a modification of an aptamer or antibody targeting the cancer cells (claims 4 & 14). Applicant further claims the medicament containing black phosphorus nanosheet further comprises a pharmaceutically acceptable adjuvant (claims 10 & 20).
The scope of the claimed surface modification for enhancing targeting efficiency and/or stability is vast encompassing any possible chemical modification of black phosphorus nanosheets (see instant claims 2-4). The scope of adjuvant in the context of treating cancer encompasses a vast number of species ranging from therapies (e.g. chemotherapy), proteins (e.g. monoclonal antibodies), nucleic acids (e.g. hTERT siRNA), and a vast number of small molecules.
Disclosure of the Prior Art:
The prior art describes various modifications for black phosphorus nano sheets such as Chen et al. (“Biodegradable Black Phosphorus Nanosheets Mediate Specific Delivery of hTERT siRNA for Synergistic Cancer Therapy,” 2018, ACS; ACS Applied Materials and Interfaces, Vol. 10, pp. 21137-21148)1 teaching that: that: “Then, the positively charged poly(ethylene glycol)-amine (5 kDa) was electrostatically bound to the naked BP nanosheets to improve their biocompatibility and physiological stability. The PEGylated BP (PBP) nanosheets were then subjected to electrostatic adsorption of branched PEI (1.8 kDa) to prepare PEG and PEI dual-functionalized BP (PPBP).” (p. 21140, col. 2, lines 12-18).
Tao et al. (“Black Phosphorus Nanosheets as a Robust Delivery Platform for Cancer Theranostics,” 2016, WILEY-VCH; Advanced Materials, Vol. 29, Issue 1, Article 201603276, pp. 1-9)2 teaches “To further demonstrate that PEG-NH2 or other functionalized PEG-NH2 such as folic acid (FA)-PEG-NH2 could be successfully coated on the surface of BP NSs, we tested the Fourier transform infrared spectra (FT-IR) and scanning transmission electron microscopy (STEM) with energy dispersive X-ray spectroscopy (EDS) mapping of elements. With an absorption band at ~ 2900 cm-1 that was attributable to the CH vibration in the PEG segment and characteristic stretching vibration at ˜1637–1653 cm-1 from the amide bonding within FA structure, the coating of PE-NH2 or FA-PEG-NH2 was confirmed.” (p. 4, col. 1, lines 6-16).
WANG (US 2017/0174516 A1) teaches titanium ligand-modified black phosphorus nanosheets modified with p-toluenesulfonate groups (see whole document, particularly ([0001], [0007]-[0016]). And teaches - “In yet another aspect, the present invention provides use of the titanium ligand-modified black phosphorus or the composition in the preparation of photodynamic therapeutic agent or photothermal therapeutic agent for killing cancer cells.” ([0033]).
The examiner finds no prior art teaching black phosphorus nanosheets in “passive package modification based on liposomes”, “a peptide modification” or “a modification of an aptamer or antibody targeting the cancer cells.” (instant claims 3-4, 13 & 14).
Regarding the Adjuvant, the prior art teaches adjuvants in the context of cancer treatment, include that: “Several types of adjuvant treatment are available, including, but not limited to: endocrine treatment, also called hormone treatment (for hormone receptor positive tumors); different chemotherapy regimens; and antibody and antibody-based treatments, based on novel agents like Herceptin™ (HER-2-specific antibody).” (US 8,367,336 – col. 3, lines 14-19). REED (US 2013/0084307 A1) teaches “The present invention in its several embodiments is directed to compositions and methods that advantageously employ the synthetic glucopyranosyl lipid adjuvant (GLA) as an adjuvant and vaccine component.” ([0011], [0017]).
BANTIA (US 2014/0378482 A1) teaches that “An adjuvant is an agent administered to potentiate the immune response to an antigen and/or modulate it towards a desired immune response. An endogenous adjuvant is a compound or molecule naturally occurring within the cell or tissue that likewise enhances an immune response by stimulating innate immunity, thus possessing the capacity to potentiate an effect of some triggering event or agent. Endogenous adjuvants play a central role in alerting the immune system to potential danger and promote response to infection, transplantation, tumor, and autoimmunity.” ([0003]). And that: “the present disclosure further provides methods and compositions useful for antiviral, antibacterial and anticancer effects by administration of a combination of one or more PNP inhibitors and one or more agents identified as endogenous adjuvants selected from inosine, deoxyinosine, guanosine, deoxyguanosine, NAD and dGTP.” ([0047]).
JEFFORD (US 2016/0158193 A1) taches that: “The present invention relates to adjuvant compounds for use in tyrosine kinase inhibitor therapy for the treatment of cancer,[…].” ([0002]). And that: “Thus, in a first aspect of the present invention there is provided a 1,2,4-trioxane of formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof for use as an adjuvant for a tyrosine kinase inhibitor to enhance the activity of said tyrosine kinase inhibitor in a method for the treatment of a patient suffering from cancer: […].” ([0010]).
NUNES (US 2016/0166683 A1) teaches that: “Another modality of treatment is adjuvant chemotherapy, which consists in administering chemotherapy drugs to the patient, alone or in association with other drugs, after surgery, with the purpose of blocking the formation or development of tumors close or far from the main location, or finally, to reduce the tumor growth rate, in the cases of micro metastases or metastases refractory to treatment.” ([0012]). And that: “Many studies associate the use of THC as adjuvant in the treatment of cancer patients, with improvement of mood and stimulation of appetite, as well as weight gain.” ([0077]). And further that: “Exogenous cytokines, such as the interferons and interleukins (IL-12, IL-2), among others, are routinely used alone, or, as it is more common in the state of the art, in association or combination with other chemotherapy drugs to maximize the therapeutic effect in the treatment of chronic systemic diseases, such as cancer, though its use alone or in combination with other drugs has some practical disadvantages because of their high toxicity levels. This type of therapeutic strategy is called adjuvant immunotherapy.” ([0128]).
Disclosure of the Instant Application:
The instant Specification discloses that: “The technical solution adopted by the present invention is as follows: the preset invention provides use of phosphorus based material in preparation of medicament for treating tumors, the phosphorus-based material is material which is convertible to produce phosphate ions in an acidic environment, and the phosphorus-based material can be converted by tumor cells phagocytosis to produce phosphate ions to change the intracellular environment and extracellular environment , thereby inhibiting proliferation of the tumor cells and inducing death of the tumor cells.” (p. 2, [0007]).
And that: “Preferably, the phosphorus-based material is subjected to surface modification for enhancing the targeting efficiency and/or stability. Wherein the surface modification for enhancing stability includes but is not limited to passive package modification based on liposome or polymer molecule, etc., ligand modification based on coordination bond, and the like; the surface modification for enhancing the targeting efficiency includes but is not limited to modification using compound like folic acid, etc., modification using peptide like cell penetrating peptides, etc., and modification of aptamer or antibody and the like targeting the cancer cells. By a targeting modification to surface of the phosphorus-based material, the amplification and metastasis of the cancer cells or tumor cells can be inhibited more effectively, thereby the recurrence of the cancer cells or the tumor cells can be prevented more effectively, further improving the therapeutic effect.” [emphasis added](p. 3, [0010]).
And further that: “Preferably, the phosphorus-based material can be used as a single preparation; or the phosphorus-based material is used as an active ingredient, and a pharmaceutically acceptable adjuvant is added to jointly prepare a medicament for treating tumors; furthermore, other anti-tumor active ingredients can also be added, to achieve a synergistic effect. Specifically, a clinically acceptable dosage form can be made in accordance with the conventional processes, including tablets, capsules, pilulas, granules, sustained-release preparations, controlled-release preparations or injection preparations, etc., which are for clinical use. Wherein, the proportion of the phosphorus-based material in the combined medicament depends on the specific needs, the specific addition amount of the phosphorus-based material may be 0.01 % to 99.99%, preferably 20% to 99.99%, further preferably 30% to 80%.” (paragraph bridging pp. 3-4, [0011]).
And further that: “The above phosphorus-based material is used in the preparation of a medicament for treating tumors, the administration manner for the prepared medicament may be intravenous administration, or directly placed within the tumor and around the tumor. Specifically, the phosphorus-based material may be used in the preparation of a medicament for treating primary or secondary cancers and sarcomas or carcinosarcomas originated from brain, blood, mammary gland, pancreas, uterus, endometrium, uterine cervix, kidney, liver, gall bladder, head and neck, oral cavity, thyroid gland, skin, mucosa, gland, blood vessel, liver, lung, esophagus, ovary, prostate, osseous tissue, lymph node, urinary bladder, colon or rectum of human and animals. The tumor cells involved in the specific effects include but are not limited to human breast cancer cell MCF-7, human cervical cancer cell Hela, liver cancer cell HepG2, human non-small cell lung cancer cell A549, acute promyelocytic leukemia cell NB4, human brain glioma cell A 172, human glioma cell LN-18, etc. The specific dose in the course of the treatment can be determined according to the type of the phosphorus-based material included in the medicament, the type of the targeted tumors and the administration manner, etc.” (p. 4, [0012]).
The Specification discloses that: “Firstly, a black phosphorus nanosheet having bioactivity was prepared by liquid phase stripping method. The specific steps comprise: in an air free environment, a certain amount of black phosphorus crystals were ground and dispersed in a solvent, then sealed, wherein a solvent could be various organic solvents, such as N-methyl pyrrolidone (NMP), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), anhydrous ethanol, isopropanol, etc.; then black phosphorus solution was stripped ultrasonically by means of probe ultrasound, water bath ultrasound or sequential action of the two, to prepare a black phosphorus sheet having bioactivity. The effect of the striping can be adjusted by changing an action mode of ultrasound and frequency of ultrasound, etc., the efficiency and yield of the stripping can also be improved in conjunction with other stripping techniques such as thermal separation technique, ion intercalation technique, etc.” (p. 6-7, [0025]).
The Specification discloses Examples including that: “The black phosphorus sheet was prepared according to the liquid phase stripping method as described above. Furthermore, the obtained black phosphorus sheet can also be subjected to a surface coordination or targeting modification, to enhance the stability and targeting efficiency of the black phosphorus sheet. The obtained two-dimensional black phosphorus (comprising the bared two-dimensional black phosphorus and modified two-dimensional black phosphorus) was dispersed in a suitable solvent, such as organic solvents of N-methyl pyrrolidone (NMP), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), anhydrous ethanol, isopropanol, etc., to achieve a long-stem storage of the material.” (p. 7, [0026]). And that: “Different types of human cancer cells (including cervical cancer cell, breast cancer cell and non-small lung cancer cell) and normal cells (choosing human bone marrow mesenchymal stem cell) were cultivated in advance. After the cells were counted, they were implanted in multi-well plates, culture medium was added, the cells were cultivated to grow. Specifically, the human cancer cell strains could be implanted into a 96-well plate at a density of 5000 cells/well, and four repeated wells were made for each group, the culture medium per well was 100 μL DMEM containing 10% FBS, the cells were placed in a 37°C incubator, and cultivated under the condition of 5% CO2 and saturated humidity for 24 hours.” ([0029]). And that: “The black phosphorus sheet with proper size was chosen for washing, specifically the black phosphorus nanosheet with thickness of 2-10 nm and length and width of 20-300 nm was chosen to facilitate cell endocytosis. Then, it was diluted in accordance with a released dilution method, such that when the volume in the culture well was 100 μl, the concentration of the medicament was 0.125, 0.25, 0.5, 1, 2, 4, 8, and 16 μg/ml, respectively, the control group was a culture medium of medicament without addition of the black phosphorus sheet. The cells were placed in a 37°C incubator, and cultivated under the condition of 5% CO2 and saturated humidity for 24 hours and 48 hours, then the original culture medium was discarded, and 100 μl of CCK8 working fluid was added and incubated for I hour, then the OD values were detected at A450 nm, the cell survival rate was calculated from the OD value of each well.” ([0030]).
The Specification discloses that: “As shown in Figs 1, 3, 5, and 7, in the cell proliferation detection experiment, the black phosphorus nanosheet was applied on three types of cancer cells: mammary gland cancer cell, cervical cancer cell and non-small lung cancer cell for 24 hours and 48 hours, then the black phosphorus nanosheet demonstrated concentration dependent cell proliferation effect to the three types of cancer cells, namely, the higher the concentration of the black phosphorus nanosheet was, the more evident inhibitory effect to the cancer cells was. After being cultivated for 48 hours, when the concentration of black phosphorus nanosheet was 0.5 μg/ml, the proliferation rate of the breast cancer cells was inhibited by about 50% (as shown in Fig. 1 ); when the concentration of the black phosphorus nanosheet was about 1 μg/ml, the inhibition rate on the proliferation of cervical cancer cells was up to 50% (as shown in Fig. 3); when the concentration of the black phosphorus nanosheet was about 2 μg/ml, the inhibition rate on the proliferation of non-small lung cancer cell was up to about 50% (as shown in Fig. 5). However, for the normal cells and the human mesenchymal stem cells, after being cultivated for 24 hours, the survival rates of the cells treated with the black phosphorus nanosheet at each concentration were all more than 90%. After being cultivated for 48 hours, the black phosphorus nanosheet at low concentration (less than 4 ug/ml) had no significant inhibition on the proliferation of the normal cells, and the survival rates of the cells ware more than 80% (as shown in Fig. 7). Thus, it can be seen that, the black phosphorus nanosheet could significantly inhibit the proliferation of cancer cells at lower dose; with the same dose, the inhibitory effect on the proliferation of normal cells by the black phosphorus nanosheet was far less than that on the cancer cells.” (pp. 9-10, [0036]).
Discussion:
MPEP §2163(I)(A) makes clear that: “There is a presumption that an adequate written description of the claimed invention is present when the application is filed. In re Wertheim, 541 F.2d 257, 263, 191 USPQ 90, 97 (CCPA 1976) ("[W]e are of the opinion that the PTO has the initial burden of presenting evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims."). However, as discussed in subsection I, supra, issues of adequate written description may arise even for original claims, for example, when an aspect of the claimed invention has not been described with sufficient particularity such that one skilled in the art would recognize that the inventor had possession of the claimed invention at the time of filing. The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional or known in the art.”
MPEP 2163(II)(A)(3)(a)(ii) makes clear that: “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted)."). - A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. […] Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) […] Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. For example, in the molecular biology arts, if an applicant disclosed an amino acid sequence, it would be unnecessary to provide an explicit disclosure of nucleic acid sequences that encoded the amino acid sequence. Since the genetic code is widely known, a disclosure of an amino acid sequence would provide sufficient information such that one would accept that an inventor was in possession of the full genus of nucleic acids encoding a given amino acid sequence, but not necessarily any particular species. Cf. In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed. Cir. 1993) and In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994). If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph.
In the instant case the rejected claims are broadly directed to “black phosphorus nanosheet is subjected to surface modification for enhancing targeting efficiency and/or stability.” (claims 2-4 & 12-14). And “a medicament containing black phosphorus nanosheet” that is administered in a therapeutically effective amount for treating tumors (claims 1 & 11), and further “wherein the medicament […] further comprises a pharmaceutically acceptable adjuvant.” (claims 10 & 20). The as-filed Application describes two species of possible compounds that could be used for modification of black phosphorus nanosheet including folic acid and peptide like cell penetrating peptides, however the Specification does not provide any guidance as to how one would actually perform such modification. There are no examples of any such modification. The number of species within the scope of the claimed modification(s) is vast and the Specification discloses two species without guidance to how such a modification should be achieve. The prior art does teach specific cases of modification(s) of black phosphorus nanosheets but are specific cases not described/or disclosed as usable with the instantly claimed invention. Therefore, Applicants were not in possession of a reasonable (representative) number of species within the scope of the claimed modification(s) (“surface modification for enhancing targeting efficiency and/or stability”), and the claims are properly rejected as failing to comply with the written description requirement, as the claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding the claimed “pharmaceutically acceptable adjuvant” the as-file Application discloses zero examples, and provides no guidance to any species of said adjuvant(s). The number of species of adjuvants used in cancer therapy is vast encompassing numerous different classes from chemotherapy to radiotherapy to proteins, nucleic acids, and a vast number of small molecules. The as-filed Application not providing any species of said adjuvant or guidance to the same, the claims are Therefore, Applicants were not in possession of a reasonable (representative) number of species within the scope of the claimed said adjuvant(s), and the claims are properly rejected as failing to comply with the written description requirement, as the claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating tumor cells in vitro, does not reasonably provide enablement for treating tumor cells in vivo and particularly in human patient. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d1400 (Fed. Cir. 1988). Among these factors are: 1) scope or breadth of the claims; 2) nature of the invention; 3) relative level of skill possessed by one of ordinary skill in the art; 4) state of, or the amount of knowledge in, the prior art; 5) level or degree of predictability, or a lack thereof, in the art; 6) amount of guidance or direction provided by the inventor; 7) presence or absence of working examples; and 8) quantity of experimentation required to make and use the claimed invention based upon the content of the supporting disclosure.
Scope or breadth of the claims
The scope of the claimed invention is described herein above and incorporated herein by reference.
Nature of the Invention
The nature of the claimed invention is directed at cancer treatment, and particularly “relates to the technical field of medicament, and in particular, to use of phosphorus-based material in preparation of medicament for treating tumors.” (Specification, p. 1, [0002]).
Relative level of skill possessed by one of ordinary skill in the art
The ordinary level of skill in the art pertaining to cancer therapy is relatively high requiring an advance degree (e.g. Masters/PhD level of education), and encompasses laboratory medical research (e.g. in vitro, and in vivo animal) as well as human medical studies (e.g. clinical trials).
State of, or the amount of knowledge in, the prior art
The state of knowledge and level thereof in the prior art as small encompassing very few studies of cancer therapy using black phosphorus nanosheets in vitro and in vivo (rat/mouse model studies). The examiner is not aware of any human clinical trials for cancer treatment using black phosphorus nanosheets. The prior art is discussed above and incorporated herein by reference.
Level or degree of predictability, or lack there of, in the art
The level of predictability in the art pertaining to cancer treatment, and particularly human cancer treatment is very low with most clinical trials for treating cancer in humans failing.
Amount of guidance or direction provided by the inventor
The inventor describes the action of black phosphorus nanosheet in the context of the claimed invention as follows: “ The beneficial technical effect of the present invention is: the present invention provides use of phosphorus-based material in the preparation of medicament for treating tumors, wherein the phosphorus-based material is a material which is convertible to produce phosphate ions in an acidic environment. The phosphorus-based material has a specific bioactivity, which is conversible to produce a large number of phosphate ions after being phagocytized by the tumor cells, changing the intracellular environment and extracellular environment of the cells, and then inhibiting proliferation of the tumor cells and inducing death of the tumor cell. Specifically, due to an enhanced permeability and retention effect (EPR) of the tumor tissues and/or due to a targeting effect of its surface, etc., the phosphorus-based material is accumulated in the tumor tissue microenvironment, and/or after being ingested by the tumor cells via endocytosis, its conversion is accelerated due to the slightly acidic microenvironment inside and outside the tumor cells, and a large number of phosphate ions and other active products (i.e., unstable intermediate products, such as active radicals, reactive oxygen species, etc.) are instantaneously produced in the accelerated conversion process, named as "Ionic Bomb Effect", further inducing a change in internal and external microenvironments of the tumor cells, and promoting a non-specific phosphorylation of proteins, thereby disrupting mitosis, inhibiting proliferation, and ultimately inducing death of the tumor cells. Meanwhile, for the normal cells, due to their slower division activity and slightly neutral intracellular and extracellular microenvironment, the conversion of the phosphorus-based material in the normal tissues and cells is slow, and the phosphate ions which are slowly released in this mild conversion process have a very high biocompatibility, resulting in a mere effect on the normal tissues and cells. In conclusion, the whole solution is simple and efficient, the phosphorus-based material has specificity and targeting efficiency in the course of treating cancers, this specific killing process against the tumor cells may be referred to as "Bioactive Phosphorus-based Therapy", and abbreviated as "Bioactive Phosphorus-based Therapy (BPT)".” (pp. 4-5, [0013]).
Presence or absence of working examples
The inventor provides working examples in vitro for treating cancer cells, as discussed above and incorporated herein by reference (see Specification, [0032] through [0041]). The inventor provides no in vivo studies, including any animal model or human studies.
Quantity of experimentation required to make and use the invention
The amount of experimentation required for treating tumors in vivo and particularly in human patient is an undue level of experimentation. Particularly, the level of knowledge is low encompassing very few cancer treatment studies including black phosphorus nanosheets, and while the inventor does provide some guidance as to how the invention is intended to work (see, Specification, [0013]), the number of working examples in few encompassing only in vitro studies of cancer cells. Therefore, the level of skill for treating tumors in vivo and particularly in human patient is an undue level of experimentation. And the claims are properly rejected as not being enabled for the same, as the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims
To emphasize this point the Examiner points Applicants to "Genentech, 108 F.3d at 1366 and Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966)" which states,
"a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
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 5, 8, 15 and 18 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 pre-AIA the applicant regards as the invention.
Claims 5 and 15 are rejected as being indefinite for reciting “wherein the addition amount of black phosphorus nanosheet used in the medicament containing black phosphorus nanosheet is 1% to 99.99%, preferably 30% to 80%.”
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, claims 5 and 15 each recites the broad recitation “the medicament containing black phosphorus nanosheet is 1% to 99.99%”, and the claim also recites “preferably 30% to 80%” which is the narrower statement of the range/limitation. The claim(s) 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. Appropriate clarification is required.
Additionally, it is unclear if the percentage (“1% to 99.99%, preferably 30% to 80%.”) is by weight, volume or another measure. Appropriate clarification is required.
Claim 8 and 18 are rejected as being indefinite because the claim recites “wherein the black phosphorus nanosheet is used as a single preparation.” where it is unclear what exactly “used as a single preparation” is limited to. The claim could be interpreted as a single administration of a composition containing black phosphorus nanosheet, or as multiple administrations of a composition consisting of black phosphorus nanosheet. Appropriate clarification is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 6-14, and 16-20 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Chen et al. (“Biodegradable Black Phosphorus Nanosheets Mediate Specific Delivery of hTERT siRNA for Synergistic Cancer Therapy,” 2018, ACS; ACS Applied Materials and Interfaces, Vol. 10, pp. 21137-21148).
Applicant Claims
Applicant claims a method of treating tumors consisting of administering a therapeutically effective amount of a medicament containing black phosphorus nanosheet (instant claim 1).
Claim interpretation: The examiner is interpreting administering as applying to in vitro and in vivo studies.
Disclosure of the Prior Art
Chen et al. discloses biodegradable black phosphorus nanosheets mediated specific delivery of hTERT siRNA for synergistic cancer therapy (title, see whole document), and particularly “Human telomerase reverse transcriptase (hTERT) has been found to be closely related to tumor transformation, growth, and metastasis. Thus, the delivery of hTERT small interfering RNA (siRNA) is an important approach for cancer gene therapy. However, the single anticancer effect of gene silencing is often limited by poor specificity or low efficiency in siRNA delivery and release. In this work, we present small and thin black phosphorus (BP) nanosheets as a biodegradable delivery system for hTERT siRNA. The BP nanosheets prepared with poly(ethylene glycol) (PEG) and polyethylenimine (PEI) modification (PPBP), exhibited high siRNA loading capacity and robust cell uptake. The PPBP nanosheets also exhibited potent photodynamic therapy/photothermal therapy (PDT/PTT) activities when exposed to different wavelengths of laser irradiation. More importantly, PPBP nanosheets underwent a gradual degradation when presented in a mixture of low pH and reactive oxygen species (ROS)-rich environment. The degradation of PPBP was strengthened especially after local and minimal invasive PDT treatment, because of excessive ROS production. Further delivery and release of siRNA to the cytoplasm for gene silencing was achieved by PEI-aided escape from the acidic lysosome. Thus, PPBP-siRNA efficiently inhibited tumor growth and metastasis by specific delivery of hTERT siRNA and a synergistic combination of targeted gene therapy, PTT and PDT.” [emphasis added](abstract).
Chen et al. discloses that: “Then, the positively charged poly(ethylene glycol)-amine (5 kDa) was electrostatically bound to the naked BP nanosheets to improve their biocompatibility and physiological stability. The PEGylated BP (PBP) nanosheets were then subjected to electrostatic adsorption of branched PEI (1.8 kDa) to prepare PEG and PEI dual-functionalized BP (PPBP).” (p. 21140, col. 2, lines 12-18)(instant claims 2-4, 12-14).
Chen et al. discloses that: “The synergistic PDT, PTT, and gene silencing effects of PPBP-siRNA were verified in vitro on HeLa cells. First, the cytotoxicity of PPBP was examined by the CCK-8 assay after 48 h of incubation. The non-siRNA-loaded PPBP exhibited good safety even at 50 µg mL-1 BP […].” (p. 21143, §3.4. Synergistic Effects of PPBP-siRNA in Vitro). The examiner notes HeLa cells are cervical cancer cells (instant claims 1, 6, 11 & 16).
Chen et al. discloses that: “To further verify the enhanced suppression effect resulting from the synergistic combination of gene therapy, PTT and PDT, each individual therapeutic effect was examined. First, PPBP-siRNA was transfected into HeLa cells to ascertain whether the PPBP-siRNA could silence hTERT gene expression. Forty-eight hours after the treatment of HeLa (0-30 µg mL-1), cells with PPBP-siRNA followed by 808 and 660 nm irradiation, hTERT mRNA was determined by real-time RT PCR. PPBP-siRNA downregulated the mRNA expression of hTERT in a concentration-dependent manner (0, 5, 10, 20, and 30 µg mL-1, Figure S13a, Supporting Information).” (p. 2144, col. 1, lines 1-12)(instant claims 1, 9, 11 &19). The examiner notes that the siRNA that silences the hTERT gene expression is considered an adjuvant, a substance that increases the efficacy of the PPBP (instant claims 1, 10, 11 and 20).
Chen et al. discloses that: “Biodistribution of PPBP-siRNA was investigated in a tumor-bearing animal model. Mice were injected with 1 mg kg−1 of Cy7-labeled PPBP-siRNA or free Cy7-siRNA. In vivo NIR fluorescence imaging revealed an increase in fluorescence intensity in the tumor 24 h after administration of PPBP-siRNA (Figure 6a). In addition, the main organs and tumors were harvested, and ex vivo NIR imaging was performed. The results revealed that PPBP-siRNA robustly accumulated in the lungs and tumor, whereas free Cy7-siRNA did not show obvious selectivity towards the tumor (Figure 6b). Quantitative analysis of mean fluorescence intensity (MFI) further confirmed that PPBP-siRNA was more effectively distributed in the tumor (Figure 6c).” (p. 21144, col. 2, § 3.5. Tumor Targeting and Synergistic Therapeutic Effects of PPBP-siRNA in Vivo)(instant claims 1, 7-8, 11, 17 and 18).
Claims 1-4, 6, 8-14, 16, 18-20 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Tao et al. (“Black Phosphorus Nanosheets as a Robust Delivery Platform for Cancer Theranostics,” 2016, WILEY-VCH; Advanced Materials, Vol. 29, Issue 1, Article 201603276, pp. 1-9).
Applicant Claims
Applicant claims are discussed above.
Disclosure of the Prior Art
Tao et al. discloses black phosphorus nanosheets for cancer theranostics (diagnosis and therapy/treatment)(title, see whole document), and particularly that: “Herein, we designed a theranostic delivery platform based on 2D BP NSs [black phosphorus nanosheets] (Figure 1a), studied their biological activities by screening the endocytosis pathways in tumor cells, and finally applied this BP delivery platform in cancer theranostics. BP NSs were synthesized by a modified mechanical exfoliation method from bulk BP and were then functionalized with positively charged polyethylene glycol–amine (PEG-NH2) via electrostatic adsorption to improve their biocompatibility and physiological stability. The developed PEGylated BP NSs could load theranostic agents with high efficiency, such as doxorubicin (DOX) for chemotherapy and cyanine7 (Cy7) for in vivo near-infrared (NIR) imaging. The endocytosis pathways of PEGylated BP NSs were revealed with a final concentration in lysosomes (Figure 1b). With excellent biocompatibility, DOX-loaded PEGylated BP NSs exhibited enhanced antitumor effects (i.e., photothermal-, chemo-, and biological response-induced therapy) both in vitro and in vivo. Therefore, our study demonstrated the promising use of BP as an innovative 2D platform for theranostic delivery and revealed the biological activities of PEGylated BP NSs in cancer cells for the first time, which we expect will provide insights for deep understanding of the emerging 2D nanomaterials.” (p. 1, col. 2, 2nd paragraph; p. 2, Figure 1)(instant claims 1-4, 6, 8-14, 16, 18-20).
Tao et al. teaches that: “To further demonstrate that PEG-NH2 or other functionalized PEG-NH2 such as folic acid (FA)-PEG-NH2 could be successfully coated on the surface of BP NSs, we tested the Fourier transform infrared spectra (FT-IR) and scanning transmission electron microscopy (STEM) with energy dispersive X-ray spectroscopy (EDS) mapping of elements. With an absorption band at ~2900 cm-1 that was attributable to the CH vibration in the PEG segment and characteristic stretching vibration at ~1637–1653 cm-1 from the amide bonding within FA structure, the coating of PE-NH2 or FA-PEG-NH2 was confirmed.” (p. 4, col. 1, lines 6-16).
Tao et al. further discloses that: “In order to promote the therapeutic efficiency and construct specific targeting delivery systems, we also introduced targeting modified BP-PEG-FA NSs to act as model nano-carriers for DOX due to the specific binding ability between FA and folate receptor overexpressed on many cancer cells, a finding that was also demonstrated by many groups as well as by our previous studies. […] As shown in Figure S19 (Supporting Information), the cellular DOX fluorescence intensity in HeLa cells after 1 h of incubation with BP-PEG-FA/DOX NSs was significantly higher than BP-PEG/DOX NSs, proving a higher cellular uptake efficiency of BP-PEG-FA/DOX NSs. Furthermore, the in vitro cellular toxicity of BP-PEG-FA NSs as photothermal agents and BP-PEG-FA/DOX NSs as chemotherapy agents was both effectively enhanced compared with that of BP-PEG NSs and BP-PEG/DOX NSs, also indicating the good in vitro targeting effect of BP-PEG-FA NSs. Taken together, the results indicated that PEGylated BP NSs could be utilized to develop a versatile and functionalized delivery platform and that they are very promising for application in cancer theranostics due to the excellent PTT effect, high-loading efficiency, and especially low toxicity.” (paragraph bridging pp. 4-5).
Tao et al. discloses that: “We incubated pre-treated HeLa cells (30 × 10-6 M free CQ, 24 h incubation) with BP-PEG NSs and BP-PEG-FA NSs at low concentrations (5, 10, and 25 µg mL-1), as well as HeLa cells without pre-treated (i.e., free from CQ). After 4 h of incubation with these NSs, HeLa cells were washed with PBS three times, placed into medium, and then irradiated with an 808 nm NIR laser at 1.0 W cm−2 for 10 min. As expected, the cell viability decreased in the presence of CQ molecules in both BP-PEG NSs and BP-PEG-FA NSs groups compared with the CQ-free BP-PEG NSs and BP-PEG-FA NSs groups (Figure 3h). Moreover, free CQ did not show observable toxicity to HeLa cells at our tested concentration. Thus, the therapeutic effects could be caused by the inhibition of lysosomes and blockade of the fusion between autophagosomes and lysosomes under the effect of CQ, which may reduce the degradation of PEGylated BP NSs. We further introduced DOX-load NSs for the enhanced therapy of cancer in vitro. Even at a low DOX concentration (5 μg mL−1), the cell viability in groups treated with three factors (NIR, CQ, and DOX) was significantly decreased because of the synergistic effect compared with that in previous groups. Until now, we confirmed the excellent in vitro therapeutic effect of these PEGylated BP NSs, which were attributed to the PTT effect triggered by the NIR irradiation of BP-based NSs, DOX-induced chemotherapy, and CQ-mediated inhibition of lysosomes and autophagy.” (paragraph bridging pp. 5-6).
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (“Biodegradable Black Phosphorus Nanosheets Mediate Specific Delivery of hTERT siRNA for Synergistic Cancer Therapy,” 2018, ACS; ACS Applied Materials and Interfaces, Vol. 10, pp. 21137-21148) in view of Tao et al. (“Black Phosphorus Nanosheets as a Robust Delivery Platform for Cancer Theranostics,” 2016, WILEY-VCH; Advanced Materials, Vol. 29, Issue 1, Article 201603276, pp. 1-9) and Xu et al. (“Delivery of Paclitaxel Using PEGylated Graphene Oxide as a Nanocarrier,” 2014, ACS; ACS Applied Materials and Interfaces, Vol. 7, pp. 1355-1363).
Applicants Claims
Applicant claims are discussed above.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Chen et al. discloses biodegradable black phosphorus nanosheets mediated specific delivery of hTERT siRNA for synergistic cancer therapy, as discussed above and incorporated herein by reference.
Tao et al. discloses black phosphorus nanosheets for cancer theranostics, as discussed above and incorporated herein by reference. Tao et al. further teaches that: “We expect that the BP NSs may have great possibility to enable efficient loading of theranostic agents, similar to graphene, MoS2, or other theranostic tools, because of the atomically thin area 2D structure and relatively large surface” (p. 1, col. 2, lines 12-15).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Chen et al. is that Chen et al. does not expressly teach the “addition amount of the black phosphorus nanosheet used in the medicament nanosheet used in the medicament containing black phosphorus is 1% to 99.99%” (instant claims 5 & 15).
Xu et al. teaches delivery of paclitaxel using PEGylated Graphene Oxide as a nanocarrier (title, see whole document), and teaches that: “Thus, GO-PEG-PTX was evaluated to contain about 37 wt % of GO and 63 wt % of PEG-PTX” (p. 1361, col. 1). Graphene is a similar nanosheet to black phosphorus as suggested by Tao et al., and therefore the Xu et al. suggest producing a anticancer medicament encompassing ~37 wt% of nanosheet (e.g. black phosphorus nanosheet) within the scope of an “addition amount of the black phosphorus nanosheet used in the medicament nanosheet used in the medicament containing black phosphorus is 1% to 99.99%” (instant claims 5 & 15).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a method for the treatment of cancer using black phosphorus nanosheet compositions (medicaments), as suggested by Chen et al. and Tao et al., and including an “addition amount of the black phosphorus nanosheet used in the medicament nanosheet used in the medicament containing black phosphorus is 1% to 99.99%”, as suggested by Xu et al., and Tao et al. teaching black phosphorus nanosheets as similar to graphene, and Xu et al. teaching the amount of GO being ~ 37 wt.%.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Conclusion
Claims 1-20 are pending and have been examined on the merits. Claims 2-4, 10, 12-14, and 20 are rejected under 35 U.S.C. 112(a)(Written Description); claims 1-20 are rejected under 35 U.S.C. 112(a)(Scope of Enablement); claims 5, 8, 15 and 18 are rejected under 35 U.S.C. 112(b); claims 1-4, 6-14, and 16-20 are rejected under 35 U.S.C. 102(a)(1); and claims 1-20 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
1 Of record as cited on Applicants’ IDS dated 10/09/2024, NPL-Citation No. 5.
2 Of record as cited on Applicants’ IDS dated 10/09/2024, NPL-Citation No. 12.
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