DETAILED ACTION
Status of the Claims
Claims 19-41 are pending in the instant application. Claims 20-21, 24-25, 28-32 and 40 have been withdrawn based upon Restriction/Election. Claims 19, 22, 23, 26-27, 33, 34-39 and 41 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 .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 05/26/2020, the filing date of the EPO – EP20305548.8.
Information Disclosure Statement
The information disclosure statements submitted on 11/23/2022 and 06/03/2025 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(b)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 19, 22, 23, 33, 34-39 and 41 remain 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.
Claim 19 is rejected as being indefinite because the claim recites “A method for treating cancer in a human patient ineligible to undergo a standard-of-care treatment [..]” (in lines 1-2) which is considered indefinite because “ineligible” and “standard-of-care” are considered subjective terms. MPEP §2173.05(b)(II) makes clear that: “A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite.” In the instant case “standard-of-care” is a variable object because the “standard-of-care” for cancer treatment changes based on the discovery/introduction of new treatment options. Additionally, whether a patient is eligible or ineligible for any given treatment is subjective, particularly in edge cases (i.e. cases close to the edge of eligible/ineligible). MPEP §2173.05(b)(IV) makes clear that: “When a subjective term is used in the claim, the examiner should determine whether the specification supplies some objective standard for measuring the scope of the term. Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite.” In the instant case finds no clear distinction between eligible/ineligible in the context of the claimed invention, particularly as there is no objective standard recited in the claims. Appropriate clarification is required. Claims 22, 23, 33, and 34-39 are rejected as inheriting the above discussed limitations and doing nothing to clarify the same.
Claim 41 is rejected as being indefinite because the claim recites “A method for treating cancer in a human patient ineligible to undergo a standard-of-care treatment [..]” (in lines 1-2) which is considered indefinite because “ineligible” and “standard-of-care” are considered subjective terms, as discussed above. Appropriate clarification is required.
Response to Arguments:
Applicant's arguments filed 04/01/2026 have been fully considered but they are not persuasive.
Applicant argues that the instant Specification defines the terms “Standard-of-Care” on page 9 lines 8-18 – “The term ‘standard-of-care’ is used in the usual medical sense in the context of the invention. In the context of the invention, preferably the following combinations of Levels of Evidence and Grades of Recommendation are considered as the ‘standard-of-care’ for a given indication by a task force composed of a panel of specialists in the field, typically a medical oncologist, a radiation oncologist, possibly along with a surgical representative specialized in an organ-specific cancer:
- "I, A" and "II, A", when referring to the ESMO Clinical Practice Guidelines (see Table 1),
- "Quality of evidence: high", "strength of recommendation: strong", when referring to the ASTRO Clinical Practice Guidelines,
- "Type: evidence based"; "Evidence quality: high, benefit outweighs harm"; "Strength of recommendation: strong", when referring to the ASCO Clinical Practice Guidelines;
- the categories "1" and "2a" when referring to the NCCN Guidelines for Patients.” (p. 5). And that: “They offer, for the first time, a therapeutic solution to subjects, who, up until now, would have been considered as untreatable by multidisciplinary (oncology) teams taking into account the standard guidelines. These guidelines have been established typically by a panel of specialists in the field. Therefore, the present nanoparticles and nanoparticle aggregates offer a therapeutic solution to subjects who cannot benefit from the herein described ‘standard-of-care treatments’, typically, a standard-of-care treatment involving RT for said cancer.” (p. 5; Specification p. 11, lines 4-9). Applicant goes on to point to Exemplary embodiments (p. 14, lines 24-29 – “For example […].”).
Applicant also points to subsequent descriptions related to the following cancer indications and clinical staging locally advanced non-small cell lung carcinoma (page 15, lines 26-35), operable locally advanced esophageal cancers (paragraph linking pages 16 and 17), and glioblastoma multiforme (page 18, lines 1-9), for which the standard-of-care treatment option involving radiotherapy is presented and from there, specific values of total radiation dose given are identified in the context of the invention. Therefore, Applicant submits that the as-filed application and the terms in question set out and circumscribe particular subject matter with a reasonable degree of clarity and particularity. Indeed, abundant examples are given for standard-of-care treatment options involving radiotherapy for a given cancer indication/clinical staging (herein typically described for patients suffering from locally advanced SCCHN, locally advanced NSCLC, operable locally advanced esophageal cancers, glioblastoma multiforme ), and new total radiation doses are indicated corresponding to a radiation dose reduction of at least 85% when compared to the total radiation dose given in the context of the defined standard-of-care treatment options to optimize the benefit to risk ratio for the selected patient population.” (p. 6, 3rd paragraph).
In response the examiner argues that the Specification does not define “standard-of-care” such that one of ordinary skill would clearly understand the scope of “standard-of-care” in the context of the claimed invention. Particularly on page 9 the Specification uses the word “preferably” clearly indicating that this is not a “definition” in the context 112(b) - 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 – that limits the claimed subject matter, in this case, the patient class. The instant Specification clearly does provide guidance to what could be considered to define the patient class (e.g. 112(a) - written description) but does not define the scope of “standard-of-care” such that it is clear what Applicant regards as their invention. The examiner maintains that whether a patient is eligible or ineligible for any given treatment is subjective, particularly in edge cases (i.e. cases close to the edge of eligible/ineligible). The examiner emphasizes that this is not a 112(a) written description rejection but a rejection based on the claim language which attempts to define the patient class in a way that is considered indefinite. MPEP §2173.05(b)(II) makes clear that: “A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite.” In the instant case “standard-of-care” is a variable object because the “standard-of-care” for cancer treatment changes based on the discovery/introduction of new treatment options. Additionally, whether a patient is eligible or ineligible for any given treatment is subjective, particularly in edge cases (i.e. cases close to the edge of eligible/ineligible). MPEP §2173.05(b)(IV) makes clear that: “When a subjective term is used in the claim, the examiner should determine whether the specification supplies some objective standard for measuring the scope of the term. Some objective standard must be provided in order to allow the public to determine the scope of the claim. A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite.”
Applicant further argues that: “‘Patients unable to undergo standard-of-care treatment are typically patients for whom the standard-of-care treatment is contraindicated, or, more broadly, who are ineligible for said treatment. Patients for whom there is a high risk of intolerance to the standard-of- care treatment thus have an unfavorable benefit/risk ratio with respect to said treatment.’ Persons skilled in the art recognize ‘ineligible’ as a standard term used in a clinical setting.” (p. 6, last paragraph). And that: “A search on the clinicaltrials.gov website yields more than 500 results or trials with the term ‘ineligible’ in the trial description. Below is an example of two clinical trials with the term in the trial title.”(p. 7, 1st paragraph). And further that: “Applicant respectfully submits that the claims are definite and would be understood by those skilled in the art. Accordingly, reconsideration and withdrawal of this rejection is respectfully requested.” (p. 7, 2nd paragraph).
In response the examiner argues that the instantly rejected claims do not define “ineligible” in such a way that one of ordinary skill would clearly recognize where the line between “eligible” and “ineligible” should be. The claims are certainly not limited by clinicaltrials.gov which does not include patent claims. The issue at hand is the scope of a patent claim not a clinical trial. Therefore, the rejection is maintained.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 19, 22, 23, 26-27, 33, 34-39 and 41 remain rejected under 35 U.S.C. 103 as being unpatentable over LEVY (US 2012/0203050; published August 2012) in view of POTTIER (US 2014/0335015; published November, 2014); TODD (US 2012/0087868; published April, 2012) and Silva et al. (“Targeted therapies for the treatment of non-small-cell lung cancer: Monoclonal antibodies and biological inhibitors,” 2017, Taylor & Francis; Human Vaccines & Immunotherapeutics, Vol. 13, No. 4, pp. 843–853).
Applicants Claims
Applicant claims "A method for treating cancer in a human patient ineligible to undergo a standard-of-care treatment involving radiotherapy (RT) or in a patient at high risk of intolerance to a standard-of-care treatment involving RT, wherein the method comprises a step of administering nanoparticles and/or aggregates of nanoparticles to said patient, the nanoparticles and/or aggregates of nanoparticles comprising more than 30% by weight of at least one chemical element having an atomic number (Z) between 20 and 83, and a step of exposing the patient who has been administered with the nanoparticles and/or aggregates of nanoparticles to a total dose of ionizing radiation that is equal to or less than 85% of the total dose delivered in the standard-of-care treatment involving RT for said cancer." (instant claim 1).
Elected Species: Applicants have elected the following species in the reply filed 08/28/2025: (a) a species of cancer treated is a lung cancer; (b) a species of administration route is intra-tumoral (IT) route; (c) a species of nanoparticle and/or aggregates of nanoparticles is (i) hafnium (Hf)(i.e. at least one chemical element having an atomic number (Z) between 20 and 83, (ii) a coating material is a phosphate; and (iii) no species of targeting moiety present; (d) a species of total dose of radiation is equal to or less than 56.1 Gy; and (e) a species of at least on therapeutic agent is an immunotherapeutic agent.
Determination of the scope
and content of the prior art (MPEP 2141.01)
LEVY teaches that: "The present application relates to activable nanoparticles which can be used in the health sector, in particular in human health, to disturb, alter or destroy target cells, tissues or organs. It more particularly relates to nanoparticles which can generate a significantly efficient therapeutic effect, when exposed to ionizing radiations. The inventive nanoparticle is a metallic nanoparticle having, as the largest size, a size comprised between about 80 and 105 nm, the metal having preferably an atomic number (Z) of at least 25. The invention also relates to pharmaceutical compositions comprising a population of nanoparticles as defined previously, as well as to their uses." (abstract, see whole document).
LEVY teaches that: “The present application relates to activable nanoparticles which can be used in the health sector, in particular in human health, to disturb, alter or destroy target cells, tissues or organs. It more particularly relates to nanoparticles which can generate a surprisingly efficient therapeutic effect, when exposed to ionizing radiations such as X-Rays, γ-Rays, radioactive isotopes and/or electron beams. The inventive nanoparticle is a metallic nanoparticle having, as the largest size, a size comprised between about 80 and about 105 nm, the metal having preferably an atomic number (Z) of at least 25. The invention also relates to pharmaceutical compositions comprising a population of nanoparticles as defined previously, as well as to their uses.” ([0001])(instant claim 19 & 37, ionizing radiation).
LEVY teaches that: "Inventors herein provide powerful nanoparticles, which are surprisingly able to achieve a more efficient perturbation, alteration or destruction of target cells in vitro, ex vivo and in vivo when said nanoparticles are exposed to ionizing radiations, than nanoparticles described in the prior art, as herein demonstrated." ([0008]). By "dose enhancement" is meant that nanoparticles can enhance the effective dose of radiation ([0007]).
LEVY teaches that: “The present nanoparticles can also be advantageously administered through intratumoral” ([0023])(elected species of administering, claim 1, line 4).
LEVY teaches that: "Such a metal may be selected from gold (Au-Z=79), silver (Ag-Z=47), platinum (Pt-Z=78), palladium (Pd-Z=46), tin (Sn-Z=50), tantalum (Ta-Z=73), ytterbium (Yb-Z=70), zirconium (Zr-Z=40), hafnium (Hf Z=72), terbium (Tb-Z=65), thulium (Tm-Z=69), cerium (Ce-Z=58), dysprosium (Dy-Z=66), erbium (Er-Z=68), europium(Eu-Z=63), holmium(Ho-Z=67), iron (FeZ=26), lanthanum (La-Z=57), neonydium (Nd-Z=60), praseodynium(Pr-Z=59), and mixtures thereof." ([0097]). And that: "The metal is preferably selected from gold (Au), silver (Ag), platinum (Pt), palladium (Pd), tin (Sn), zirconium (Zr) and iron (Fe)." [emphasis added]([0098])(instant claim 1, 33, “at least one chemical element having an atomic number (Z) between 20 and 83”, Hf).
LEVY teaches that: "Inventors herein disclose that the surprising efficiency of the nanoparticles according to the present invention is mainly due to their size. A nanoparticle, the size of which is of at least 80 nm, is indeed, when exposed to ionizing radiations, capable of generating more damages to target cells than is a nanoparticle of smaller size, in particular a nanoparticle of 60 nm or less. Inventors thus herein highlight the fundamental and direct influence of the nanoparticle size on cell disturbance under ionizing radiations, the herein described sizes favouring therapeutic applications in a mammal, when said size reaches, and preferably exceeds, the 80 nm threshold (see experimental part). The largest the nanoparticle size in the herein identified range of sizes, the more efficient is their ability to generate cell damages." ([0110]). And that: "A possible explanation of this mechanism could be due to the nanoparticle ability to deliver the captured energy (ionizing radiation) in a better or different way." ([0111])(instant claim 1, “a step of exposing the patient […] to a total dose of radiation”).
LEVY teaches that: "The required doses of ionizing radiations are preferably doses comprised between about 0.05 Gray and about 16 Grays, preferably between about 0.05 Gray and about 6 Grays, for applications performed in vitro." ([0116]). (Grays= Gy), "Doses are comprised between more than about 0.05 Gray and less than about 16 or 30 Grays for applications performed, in particular locally, ex vivo or in vivo." ([0117]), and that: "Total ionizing radiations range from about 1.5 Gray up to about 85 Grays in the human according to the current practice. Additional irradiation boost of about 40 Gray may also be provided in the human, according to the current practice." ([0118])(instant claims 1, 26-27, radiation dose).
LEVY teaches that: "A strong enhancement of radiotherapy efficacy can be observed for the first time using metallic nanoparticles according to the present invention (cf. FIGS. 4A, 4B, SA and SB for example)." ([0086]). And that: "A population of metallic nanoparticles wherein the mean largest size of a nanoparticle of the population is between 80 and 105 nm, is particularly advantageous in therapy when said nanoparticles are exposed to ionizing radiations. Such nanoparticles indeed, in particular, allow an enhanced Dose Enhancement Factor (DEF)." ([0255]).
LEVY teaches that: "The nanoparticles herein described are in particular intended to be used to treat cancer where radiotherapy is a classical treatment. Such cancer may be selected in particular from the group consisting of skin cancer, including malignant neoplasms associated to AIDS, melanoma; central nervous system tumors including brain, stem brain, cerebellum, pituitary, spinal canal, eye and orbit; head and neck tumors; lung cancers; breast cancers; gastrointestinal tumors such as liver and hepatobiliarytract cancers, colon, rectum and anal cancers, stomach, pancreas, oesophagus cancer; male genitourinary tumors such as prostate, testis, penis and urethra cancers; gynecologic tumors such as uterine cervix, endometrium, ovary, fallopian tube, vagina and vulvar cancers; adrenal and retroperitoneal tumors; sarcomas of bone and soft tissue regardless the localization; lymphoma; myeloma; leukemia; and pediatric tumors such as Wilm's tumor, neuroblastoma, central nervous system tumors, Ewing's sarcoma, etc." [emphasis added]([0195])(elected species of cancer, instant claim 1, treating cancer; claim 23).
LEVY teaches that: “Preferred nanoparticles according to the invention are covered with a biocompatible coating regardless of the route of administration.” ([0122]). And that: “The biocompatible coating preferably comprises or is made of a compound selected in the group consisting of an inorganic agent, […].” ([0131]) … “Appropriate inorganic agent may be selected from the group consisting of an oxide […].” ([0132]) … “The agent comprising a function capable of conferring biocompatibility to a nanoparticle according to the present invention may have a steric function and/or an electrostatic function.” ([0136]) … “Agent with a negative electrostatic function may be selected from the group consisting of phosphate (for example a polyphosphate, a metaphosphate, a pyrophosphate, etc.), […].” ([0138])(instant claims 35, elected species of coating).
LEVY teaches that: “The pharmaceutical composition can further comprises an additional therapeutic compound, distinct from a nanoparticle or of a population of nanoparticles as herein described, also intended to treat cancer.” ([0180])(instant claim 38).
LEVY teaches that: “The nanoparticles can also be used for advanced tumors which can not be surgically removed.” ([0193])(instant claim 22).
LEVY teaches that: “A population of metallic nanoparticles wherein the mean largest size of a nanoparticle of the population is between 80 and 105 nm, is particularly advantageous in therapy when said nanoparticles are exposed to ionizing
radiations. Such nanoparticles indeed, in particular, allow an enhanced Dose Enhancement Factor (DEF).” ([0255])(instant claims 1, 26-27, lower dose of ionizing radiation).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of LEVY is that LEVY does not expressly teach the nanoparticles are hafnium oxide (HfO2)(instant claim 36, elected species; the lung cancer is non-small cell lung carcinoma (NSCLC) and the patient has a stage IIIA or stage IIIB NSCLC (instant claim 26).
POTTIER teaches “Nanoparticles of the invention comprise a metallic material at least partly covered with an hafnium oxide material or embedded therein.” (title, abstract, see whole document). And that: “Inventors further believe that the claimed combination of metallic and hafnium oxide materials may be responsible for an efficient deposit of energy within the tumor structure said deposit being responsible for the dramatical enhancement of tumor destruction in vivo when activated by radiations when compared to standard treatments.” ([0015]).
POTTIER teaches including drug molecules, such as “a compound capable to induce a biological action such as an immune response.” ([0079]).
TODD teaches that: “The invention provides nanoparticle-loaded cells and compositions useful for improved imaging and therapy, for example radio-therapy. The invention also provides methods of manufacture of nanoparticle-loaded cells, methods of administering the nanoparticle-loaded cells, and methods for treatment and/or imaging.” (title, abstract, see whole document).
TODD teaches that: “The invention, in general, provides for one or more carrier cells, carrier cell compositions, and methods of using such cells and/or compositions (e.g., mesenchymal stem cells) having nanoparticles ("nanoparticle-loaded cells") which are able to interact with electromagnetic radiation or magnetic fields. According to the practice of the present invention, it is believed that (while not being bound by any particular theory, however) the interaction of nanoparticles with electromagnetic radiation or magnetic fields enhances energy deposition to local environments. Preferably, the nanoparticles utilized in the practice of the present invention comprise a high-Z material. Additionally or alternatively, the interaction of those nanoparticles and nanoparticle-loaded cells with one or more electromagnetic radiations or magnetic fields provides opportunities for imaging of tissues and/or detection of various diseases, diseased cells, disease states and the like.” ([0013]). And that: “"Heavy metals" or "high-Z elements" as used herein
refer to metal elements with an atomic number of at least about 22, including, for example […] hafnium (Z=72) […].” ([0061]).
TODD teaches that: “In one embodiment, the disease that is treated and/or imaged is a lung cancer. Optionally, the lung cancer is small cell lung cancer. Optionally, the lung cancer is non-small cell lung cancer (NSCLC).” ([0148]). And that: “Methods of treating cancer (e.g., lung cancer, or advanced stage lung cancer) using nanoparticle-loaded cells of the present invention unexpectedly provide one or more of the following results, for example, compared to prior art treatments such as high-Z material-enhanced radiotherapy: […] the 1 year mortality rate to less than about 100% for stage IV recurrent NSCLC, to less than about 65% to about 70% for stage IIIb-IV NSCLC.” ([0154]). “the 5 year mortality rate to less than about 70% to about 85% for stage Illa, […].” ([0155])(instant claim 1, “treating cancer”; claim 26, “the patient has a stage IIIA or stage IIIB non-small cell Lung Carcinoma (NSCLC) tumor”).
Silva et al. teaches that: “The usual treatments for patients with non-small-cell lung cancer (NSCLC), such as advanced lung adenocarcinoma, are unspecific and aggressive, and include lung resection, radiotherapy and chemotherapy. Recently, treatment with monoclonal antibodies and biological inhibitors has emerged as an effective alternative, generating effective results with few side effects. In recent years, several clinical trials using monoclonal antibodies presented potential benefits to NSCLC, and 4 of them are already approved for the treatment of NSCLC, such as cetuximab, bevacizumab, nivolumab and pembrolizumab.” (abstract, see whole document)(instant claim 39). Silva et al. teaches that: “Immunotherapy with biological inhibitors and monoclonal antibodies are treatments recently applied to tumors, since they cause less damage to normal cells. This technology represents enormous contributions in the treatment of lung cancer. Monoclonal antibodies are highly specific and require that tumor cells express the target antigen, since they can only activate various mechanisms involved in the immune response, such as induction of apoptosis as well as the blockage of cell growth and transcription factors.” (paragraph bridging pp. 847-848).
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 of treating lung cancer using nanoparticles which can generate a surprisingly efficient therapeutic effect, when exposed to ionizing radiations such as X-Rays, y-Rays, radioactive isotopes and/or electron beams, the nanoparticles having, as the largest size, a size comprised between about 80 and about 105 nm, the metal having preferably an atomic number (Z) of at least 25 such as Hafnium, and a reduced total dose of radiation, as suggested by LEVY, the Hafnium nanoparticles being hafnium oxide nanoparticles as taught by POTTIER, and the lung cancer being non-small cell lung cancer (NSCLC) stage IIIa or IIIb, as suggested by TODD, and further to include a compound capable to induce a biological action such as an immune response, as suggested by POTTIER, the compound being a monoclonal antibody approved for treatment of NSCLC, such as, cetuximab, bevacizumab, nivolumab and pembrolizumab, as taught by Silva et al., since they (monoclonal antibodies) cause less damage to normal cells.
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 because it would have required no more than an ordinary level of skill in the art to apply the method suggested by LEVY/POTTIER/TODD to non-small cell lung cancer (NSCLC) in combination with approved monoclonal antibodies for treating NSCLC. 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(a).
Response to Arguments:
Applicant's arguments filed 04/01/2026 have been fully considered but they are not persuasive.
The examiner acknowledges Applicants allegation of unexpected results based on the “poster” attached. However, the claims are not limited to the “ongoing clinical trial NCT04505267” and Applicant has not convincingly mapped the data to the claims. Additionally, MPEP §716.02(c)(II) makes clear that arguments cannot take the place of evidence. And “Applicant has the burden of explaining proffered data” (MPEP §716.02(b)(II)). And particularly how exactly “The evidence relied upon should establish ‘that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.’” (MPEP §716.02(b)(I)). And any unexpected results must be commensurate with the claims which are not limited to treating recurrent non-small cell lung cancer (NSCLC) which had previously received radio therapy for treatment of the same, and claims are not limited to intratumoral injection “hafnium oxide nanoparticles” and a dose of 45 Gy (MPEP §716.02(d)).
Additionally LEVY clearly teaches that: “It has been surprisingly found by inventors that a nanoparticle made of a metal, preferably a metal having an atomic number (Z) of at least 25, and having, as the largest size, a size comprised between about 80 and 105 nm, can substantially enhance the therapeutic effect of a local irradiation intended to disturb, alter or destroy abnormal cells, tissues or organs in an animal.” [emphasis added]([0085]). And that: “A strong enhancement of radiotherapy efficacy can be observed for the first time using metallic nanoparticles according to the present invention.” ([0086]). LEVY teaches that: “A population of metallic nanoparticles wherein the mean largest size of a nanoparticle of the population is between 80 and 105 nm, is particularly advantageous in therapy when said nanoparticles are exposed to ionizing radiations. Such nanoparticles indeed, in particular, allow an enhanced Dose Enhancement Factor (DEF).” ([0255]). Therefore, the results do not appear to be unexpected relative to LEVY clearly teaching an enhanced therapeutic effect in treating cancer with nanoparticles that “substantially enhance the therapeutic effect of a local irradiation intended to disturb, alter or destroy abnormal cells” and defines a “Dose Enhancement Factor (DEF)” clearly implying a lower dose needed for the same anti-cancer effect in radiotherapy combined with the nanoparticles. And POTTIER teaches that: “Inventors further believe that the claimed combination of metallic and hafnium oxide materials may be responsible for an efficient deposit of energy within the tumor structure said deposit being responsible for the dramatical enhancement of tumor destruction in vivo when activated by radiations when compared to standard treatments.” [emphasis added]([0015]).
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that: “The claimed invention is premised on the surprising and unexpected finding that, for example, in lung cancer patients who are ineligible or at high risk of intolerance for standard-of-care radiotherapy, a total radiation dose of 45 Gy (25% less than the standard 60 Gy) in combination with nanoparticles can achieve clinically meaningful therapeutic responses. This is contrary to the established clinical understanding that dose reduction in lung cancer radiotherapy is associated with inferior outcomes.” (p. 10, 4th paragraph). And that: “Here, the early clinical data (as shown in the attached poster) demonstrates that patients receiving 45 Gy with nanoparticles exhibit clinically meaningful therapeutic responses, suggesting that the claimed regimen is not only feasible but also effective, contrary to what would be expected from the prior art or clinical practice.” (p. 10, 5th paragraph).
In response the examiner argues that the cited prior art suggests Applicants result of enhancement of radiotherapy by utilizing nanoparticles to enhance the radiotherapy (LEVY: “It has been surprisingly found by inventors that a nanoparticle made of a metal, preferably a metal having an atomic number (Z) of at least 25, and having, as the largest size, a size comprised between about 80 and 105 nm, can substantially enhance the therapeutic effect of a local irradiation intended to disturb, alter or destroy abnormal cells, tissues or organs in an animal.” [emphasis added]([0085])), and POTTIER teaches the same with hafnium oxide nanoparticles, therefore, the results do not appear to be surprising relative to the cited prior art.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (paragraph bridging pp. 10-11), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant further argues that: “The claimed invention also addresses a long-felt but unmet need for safer and more tolerable radiotherapy regimens for lung cancer patients who cannot tolerate standard doses. The reduction in total radiation dose, enabled by the use of the claimed nanoparticles, represents a significant advance in the art and is not suggested or rendered obvious by the cited references.” (p. 11, 3rd paragraph).
In response the examiner finds no objective evidence of record to support a long felt need.
MPEP §716.04 makes clear that: “Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. […]’Since the alleged problem in this case was first recognized by appellants, and others apparently have not yet become aware of its existence, it goes without saying that there could not possibly be any evidence of either a long felt need in the . . . art for a solution to a problem of dubious existence or failure of others skilled in the art who unsuccessfully attempted to solve a problem of which they were not aware.’);[…] (Although the claimed invention achieved the desirable result of reducing inventories, there was no evidence of any prior unsuccessful attempts to do so.)” “Second, the long-felt need must not have been satisfied by another before the invention by the inventor. […] (Although at one time there was a long-felt need for a ‘do-it-yourself’ window shade material which was adjustable without the use of tools, a prior art product fulfilled the need by using a scored plastic material which could be torn. ‘[O]nce another supplied the key element, there was no long-felt need or, indeed, a problem to be solved’.)” And: “Third, the invention must in fact satisfy the long-felt need.”
Conclusion
Claims 19, 22, 23, 26-27, 33, 34-39 and 41 are pending and have been examined on the merits. Claims 19, 22, 23, 33, 34-39 and 41 are rejected under 35 U.S.C. 112(b); and claims 19, 22, 23, 26-27, 33, 34-39 and 41 is rejected under 35 U.S.C. 103. No claims allowed at this time.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
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