DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 12, 2025 has been entered.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on February 21, 2025, wherein claims 1-7, 9-10, 12, and 15-17 are canceled; claims 8, 11, 13-14 and 18 are unchanged.
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 8, 11, 13-14 and 18 are pending and under examination.
Action Summary
Claims 8, 11, 13-14 and 18 rejected under 35 U.S.C. 103 as being unpatentable over Margulies et al. (US 2022/0016312 A1; cited in IDS filed on October 17, 2023) in view of Park et al. (Methods Mol Biol., 2019. Vol. 1914: 295-308) and Bihari (US 6,384,044 B1; cited in non-final office action mailed on December 19, 2023) are withdrawn. Upon further consideration, the prior arts have been revisited, reapplied, and modified.
Declarations
The declaration under 37 CFR 1.132 filed on November 12, 2025 is insufficient to overcome the rejection of claims 8, 11, 13-14 and 18 under 35 U.S.C. 103 set forth in the Office action.
In Summary, the declarant argues the claimed invention demonstrates “almost 2-fold decrease in the volume of prostate cancer tumor 14 days in mice implanted with the ZP001 formulation” that was statistically significant and would not have been expected; and argues that similar level of prostate cancer tumor volume reduction for other formulations having a similar amount of naloxone as the formulation ZP001, such as formulation including from about 3.2 mg/ml to about 5.2 mg/ml of naloxone or its salt, iron (III) sulfate, calcium phosphate, and collagen. The declarant further argues the formulations taught by Margulies, comprising naloxone hydrochloride, are not against prostate cancer, and did not observe any reduction of a volume of a tumor associated with any type of cancer for said formulations. The declarant further argues Park fails to teach the effect of naloxone or formulation comprising naloxone on prostate cancer or on a volume of prostate cancer tumor. The declarant further argues while Bihari mentions both prostate cancer and naloxone, the prior art fails to provide any data for naloxone, only suggest systemic administration, and uses only oral naltrexone in its example; thus, one would not have any expectation of success for reducing the volume of prostate cancer tumor. The declarant further argues the teachings of Bihari on column 2, line 48-50 is based on Zagon that mentions neuroblastoma rather than prostate cancer, thus, one cannot extrapolate the Zagon’s teachings for neuroblastoma to prostate cancer. The declarant further argues based on Bihari’s teachings that recites “[n]aloxone, on the other hand, has not generally proven to be effective when administered orally; it is available in a form suitable for injection and is better administered by injection” (Column 6, lines 56-58), one would have understood that naloxone injection has a) poor systemic perfusion into visceral tissues due to its 30-minute half-life and rapid degradation by the liver; b) naloxone does cross the blood-brain barrier and accumulate in the brain for achieving anti-opioid effects and treating neuroblastoma; However, that would not lead one of ordinary skill in the art to arrive at the claimed invention with a reasonable expectation of success.
In response, the declaration has been fully considered but it is insufficient to overcome the rejection of record for the reasons set forth below:
First, it is respectfully noted that the declarant asserts the ZP001 formulation of instant specification implanted to mice demonstrates unexpected prostate cancer tumor volume reducing effect, while simultaneously asserts that similar level of prostate cancer tumor volume reduction would have been expected for other formulations having a similar amount of naloxone as the formulation ZP001 of instant specification, such as a formulation including from about 3.2 mg/ml to about 5.2 mg/ml of naloxone or its salt, iron (III) sulfate, calcium phosphate, and collagen (see e.g., page 4, lists 5-7 in the declaration). To the extent declarant’s position is accepted, such assertion undermines the allegation of unexpected results because it indicates that the observed prostate cancer tumor volume reducing effect would have been reasonably expected to translate to the bone graft composition of Margulies et al. set forth in the rejection of record because also contains similar amount of naloxone. Specifically, the obviousness-type rejection of record clearly established the bone graft composition taught by Margulies et al. contains the same ingredients shown below (see e.g., [0166]):
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438
423
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, where the claimed ranges overlap or lie inside ranges disclosed by the prior art. In other words, based upon the declarant’s assertion, the bone graft composition taught by Margulies et al., which contains similar amount of naloxone, would expect to possess the same activity of decreasing volume of a prostate cancer tumor. Please note 0.01% to 2% of naloxone hydrocholoride in a solution between 0.5 mL and 12.5 mL in volume (see e.g., [0166]), it gives a range of 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride (see calculation in the rejection below). Therefore, the fact that the method of applying, such as implanting, the bone graft composition of Margulies et al. at a therapeutically effective amount to the bone of a subject that contains prostate cancer would have been obvious to a person skilled in the art for treating the bone defect caused by prostate cancer (see rejection below), implanting similar product to the bone defect caused by said prostate cancer, where prostate cancer tumor is localized or metastasized, would naturally result in that property when the bone graft composition contacts with the prostate cancer tumor in the bone. Please note MPEP 2145, II states “[t]he fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. In other words, the claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, by administering the composition under similar circumstances would naturally result in the same property. The declarant cannot simultaneously rely upon the similarity between each composition comprising naloxone to establish relevance of the data while asserting that the claimed naloxone composition exhibits unexpected properties.
Second, 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). The declarant improperly evaluate each reference individually rather than considering the combined teachings of the reference as a whole. For instance, the declarant argues Park fails to teach the effect of naloxone or formulation comprising naloxone when the rejection of record already established the naloxone composition using the bone graft composition taught by Margulies et al. (see e.g., [0166]); and the declarant argues Bihari teaches systemic administration of naloxone rather than implant when the rejection of record relies on Margulies et al. to teach the bone graft composition can be implanted (see e.g., [0061]). Each of these findings demonstrate that declarant’s improperly evaluates the references individually rather than considering the collective teachings.
In the present case, the obviousness-type rejection of record uses the combination of prior arts (Margulies et al. in view of Park et al. and Bihari) rather than each of them alone. The obviousness-type rejection under 35 U.S.C. 103 does not require that each and every claimed limitation be disclosed within a single reference. Rather, the issue is whether the collective teachings of the prior art(s) would have suggested the claimed invention to one of ordinary skill in the art with a reasonable expectation of success. Specifically, the rejection of record is form on the basis that the bone graft composition taught by Margulies et al. contains the same ingredients instantly claimed (see e.g., [0166]); said prior art further teaches the bone graft composition can be applied, such as implanted (see e.g., [0061]), to repair a bone defect caused by cancer, and the bone graft composition contains an active agent for treating cancer (see e.g., claims 8-9 and 11; [0170]), including prostate cancer (see e.g., [0025]); and the treatment of a cancer includes remission of the tumor, or reduction or elimination of at least one symptom of the tumor (see e.g., [0056]). The rejection of record further relies on Park et al. to teach that prostate cancer can metastasizes to bone (see e.g., p. 1, “Introduction” section, 1st paragraph), as well as Bihari to teach naloxone is an active agent useful for treating prostate cancer and reducing tumor size (see e.g., claims 1-2; abstract). Bihari et al. further teaches naloxone, has not generally proven to be effective when administered orally; it is available in a form suitable for injection and is better administered by injection (see e.g., Col. 6, line 56-58; Col. 2, line 34-48). In other words, the rejection of record is based upon the collective teachings of Margulies et al., Park et al., Bihari rather than their individual teaching.
In addition, the declaration asserts that that the bone graft composition of Margulies et al. are not against prostate cancer, and no reduction of tumor volume associated with any type of cancer is observed. However, Margulies et al. clearly teaches the bone graft composition applied in the method comprises an active agent for treating cancer as the human disease or condition (see e.g., claims 9 and 11); and provides definition for the term “treating” to cover “the treatment of a condition causing or associated with a bone defect. For example, a cancer. Such treatment, in a subject, such as a human or veterinary patient, includes (i) inhibiting a cancer, i.e., arresting its development; (ii) relieving a cancer or disorder, i.e., causing regression of the cancer; (iii) slowing progression of the cancer; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the cancer. For example, treatment of a cancer includes, but is not limited to, elimination of the cancer or the condition caused by the cancer, remission of the tumor, inhibition of the cancer, or reduction or elimination of at least one symptom of the tumor”(see e.g., [0056]); and further discloses that “[s]pecific type of cancer include … prostate cancer”. (see e.g., [0025]). In other words, there is clearly some teaching or suggestion in the prior art to treat prostate cancer as the condition causing or associated with a bone defect. It is respectfully noted that a prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). Therefore, the mere fact that Margulies et al. does not exemplify the treatment of prostate cancer, including reducing the tumor volume of prostate cancer, in the working examples, it does not mean the prior art as a whole criticizes, discredits, or otherwise discourages applying the bone graft composition for treating prostate cancer, including remission of the tumor or reduction or elimination of at least one symptom of the tumor. To be clear, conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019). Same logic is applicable to Bihari et al. when the declarant states there are no examples or data for naloxone in the prior art. It may well be true that Bihari does not specifically exemplify the administration of naloxone for treating cancer of the prostate in a human male patient in the working examples; However, Bihari clearly teaches the opiate receptor antagonist useful for treating prostate cancer can includes naloxone or naltrexone in the preferred embodiment (see e.g., claims 1-2).
Furthermore, the declaration asserts that the teachings of Bihari et al. (Bihari's column 2, lines 48-50) is based upon Zagon that focuses on the treatment of neuroblastoma rather than prostate cancer; and given that Bihari et al. only exemplify oral naltrexone without providing any data for naloxone, one cannot extrapolate Zagon’s teachings for neuroblastoma to prostate cancer and expect naloxone could have any effect on prostate cancer, these assertions are not found persuasive. It may well be true the treatment that works for neuroblastoma will not always work on an entirely different type of cancer; However, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. Solely to rebut declarant’s assertion that the teachings of Bihari et al. is inoperable, Bihari et al. clearly teaches naltrexone and naloxone are the preferred opiate receptor A antagonists contemplate for use in the method of treating cancer of the prostate in a human male patient (see e.g., claims 1-2); wherein said prostate to be treated has metastasized to other regions of the patient’s body than the prostate gland (see e.g., claim 6). It may well be true that Bihari et al. only exemplify the administration of naltrexone in the working examples; However, the examples disclosed therein, e.g., Example 3 and 4, clearly teaches the patients with adenocarcinoma of the prostate and hard tumor mass during a digital rectal exam were immediately started on low-dose naltrexone, and after three months, the tumor masses has shrunk until they were no longer palpable by rectal examination (see e.g., Col. 8, line 19-40). While Bihari et al. does not exemplify the administration of naloxone, the prior art clearly provides working examples demonstrating that the alternated opiate receptor A antagonist naltrexone can successfully shrunk tumor masses (see e.g., Example 3-4); and further provides teachings or suggestion to interchange one opiate receptor A antagonist for another, i.e., naltrexone with naloxone, for treating cancer of the prostate (see e.g., claims 1-2). In other words, the mere fact that Zagon teaches neuroblastoma does not make the teachings of Bihari et al. as a whole inoperable nor discourage one of ordinary skill in the art to practice the method disclosed therein. In fact, there is clearly a nexus between naloxone and prostate cancer. According to MPEP 2121, I, “[w]hen the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012)”. In this case, the declaration fails to provides any factual support, such as experimental data, technical analysis, scientific reasoning, literature evidence, or an explanation showing why a person of ordinary skill in the art would have conclude the method of Bihari et al. could not work for its intended purpose, rebuttal evidence of nonenablement supporting such assertion is respectively requested.
In view of the foregoing, the declaration is insufficient to overcome the rejection of record.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
With regard to claim 8, the term “about” is construed in light of the specification. The specification on page 2, line 25 to page 3, line 1 discloses “All numerical designations, e.g., pH, temperature, time, concentration, amounts, and molecular weight, including ranges, are approximations which are varied (+) or (-) by 10%, 1%, or 0.1%, as appropriate. It is to be understood, although not always explicitly stated, that all numerical designations may be preceded by the term ‘about’”. Therefore, the precise boundaries of the phrase “from about 3.2 mg/mL to about 5.2 mg/mL of naloxone or a salt thereof” is determine by reducing 3.2 mg/mL by 10 % (lower limit) and increasing 5.2 mg/mL by 10% (upper limit) calculated as follows:
l
o
w
e
r
l
i
m
i
t
3.2
m
g
m
L
×
10
100
=
0.32
m
g
m
L
3.2
m
g
m
L
-
0.32
m
g
m
L
=
2.88
m
g
/
m
L
u
p
p
e
r
l
i
m
i
t
5.2
m
g
m
L
×
10
100
=
0.52
m
g
m
L
5.2
m
g
m
L
+
0.52
m
g
m
L
=
5.72
m
g
/
m
L
, and that gives a range of 2.88 mg/mL to 5.72 mg/mL. Furthermore, the phrase “about two-fold” is determine to be 1.9 fold to 2.1 fold by incorporating ± 10%.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
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 8, 11, 13-14 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Margulies et al. (US 2022/0016312 A1; cited in IDS filed on October 17, 2023) in view of Park et al. (Methods Mol Biol., 2019. Vol. 1914: 295-308) and Bihari (US 6,384,044 B1; cited in non-final office action mailed on December 19, 2023).
Margulies et al. teaches a method of repairing a bone defect in a patient in need thereof, comprising applying a bone graft composition, wherein the bone defect is caused by cancer (see e.g., claims 8-9 and 11; [0170]); wherein the bone graft composition can be implanted, extruded, molded, or otherwise placed at the target repair site (see e.g., [0061]; [0175]); wherein the composition facilitates repair or regeneration of bone in a human subject (see e.g., [0054]; [0061]); the bone graft composition containing an active agent with therapeutic properties for treating disease and conditions in which it is desirable or necessary to promote bone growth either by stimulating bone formation or preventing bone destruction (see e.g., [0029]); wherein the active agent is an opioid growth factor receptor (OGFR) antagonist selected from the group consisting of naloxone, naltrexone, and a salt thereof (see e.g., [0013]); wherein the human disease or condition is a cancer, and the specific type of cancer include, inter alia, prostate cancer (see e.g., [0025]). Margulies et al. further teaches the bone graft composite material is produced by mixing an appropriate diluent containing an active agent with a powder-dry slurry that is then administered directly and locally to a site of bone injury or surgical intervention where bone graft materials are normally placed to stimulate bone formation (see e.g., [0151]). Margulies et al. further teaches the dry slurry component of the bone graft material containing the following as a percentage of weight: 5% to 12% of iron (III) sulfate, 8% to 11% calcium phosphate dibasic, 9% to 12.5% calcium phosphate tribasic, 13% to 17% hydroxyapatite, 3% to 6% beta-tricalcium phosphate, 4% to 7.5% sodium phosphate dibasic, 11% to 15% sodium carbonate, 2% to 6% calcium oxide, 4% to 6% magnesium oxide, 0.5% to 2.5% L-ascorbic acid, and 18% to 23% powdered type-I collagen (see e.g., [0166]). Margulies et al. further teaches the diluent component of the bone graft material is a solution between 0.5 mL and 12.5 mL in volume composed of the following: 0.9% saline solution, 2% to 6% of acetic acid, 0.1% to 2% citric acid monohydrate, and 0.01% to 2% of naloxone hydrocholoride (see e.g., [0166]). Please note the bone graft composite material taught by Margulies et al. is a composition comprising a salt form of naloxone, iron (II) sulfate, calcium phosphate, and collagen. Margulies et al. further teaches the compositions and the materials are for bone grafting and repairing and/or filing a void or gap in a bone (see e.g., [0029]). Margulies et al. further teaches the bone graft compositions has improved material properties and improved bioavailability of agents contained in the materials (see e.g., [0029]). Margulies et al. further teaches the target repair site can be, for example, a void, gap, or other defect in a bone or other bony structure in a body of a patient (see e.g., [0061]). Margulies et al. further teaches a working example that demonstrates the placement of the bone graft composition around the implant/polymethylmethacrylatebone cement construct adjacent to bone tissue, including tibia, after subjects undergo a resection of metastatic breast cancer tumor (see e.g., Working Example 5).
Margulies does not teach the subject in need of decreasing volume of prostate cancer tumor.
Park et al. teaches approximately 80% of advanced prostate cancer metastasizes to bone, yet the mechanisms of its selectiveness and growth in bone remain unclear (see e.g., p. 1, “Introduction” section, 1st paragraph). Park et al. further teaches a large number of animal models have been developed to aid in the study of the molecular pathways of advanced prostate cancer metastasis, including intraosseous injections that allow the implantation of tumor cells directly into a
specific site of interest, such as the femur or tibia (see e.g., p. 2, 1st to 2nd paragraph; p. 6, “3.4 Intraosseous Injection (Intratibial or Intrafemoral)”). Park et al. further teaches that since these tumors grow locally by design, the intraosseous injection is a very reliable and reproducible model to study the interaction between tumor cells and the bone marrow microenvironment, resulting in subsequent tumor growth (see e.g., p. 2, 2nd paragraph).
Bihari teaches a method of treating cancer of the prostate in a human male patient comprising administering an opiate receptor A antagonist that is naloxone or naltrexone (see e.g., claims 1-2; abstract); wherein said prostate to be treated has metastasized to other regions of the patient’s body than the prostate gland (see e.g., claim 6). Bihari et al. further teaches naloxone, has not generally proven to be effective when administered orally; it is available in a form suitable for injection and is better administered by injection (see e.g., Col. 6, line 56-58). Bihari further teaches the action of the compounds of the invention can be employed to terminate the rapid growth patterns of cancer and related abnormalities, and preventing tumor growth to continue, i.e., reducing the tumor burden (see e.g., Col. 2, line 34-48). Bihari further teaches this aspect of the invention is particularly significant in light of early diagnostic techniques which do reduce tumor size, or with procedures for tumor excision (see e.g., Col. 2, line 48-50). Bihari further teaches the patients with adenocarcinoma of the prostate and hard tumor mass during a digital rectal exam were immediately started on low-dose naltrexone, and after three months, the tumor masses has shrunk until they were no longer palpable by rectal examination (see e.g., Col. 8, line 19-40).
Please note the bone graft composite material of Margulies et al. is produced by mixing the dry slurry component with the diluent comprising 0.01% to 2% of naloxone hydrocholoride in a solution between 0.5 mL and 12.5 mL in volume (see e.g., [0166]). The actual amount of naloxone hydrocholoride can be calculated as follows:
0.01
%
→
0.01
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
0.1
m
g
/
m
L
2
%
→
2
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
20
m
g
/
m
L
, and that gives a range of 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Same logic is applicable to instant process claims, the bone graft composite material of Margulies et al. clearly comprises 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride, and that meets the structural limitations of “about 3.2 mg/mL to about 5.2 mg/mL of naloxone or salt thereof” of the claimed composition.
In the present case, the bone graft composite material/composition taught by Margulies et al. renders obvious the composition instantly claimed. Even though Margulies et al. does not specifically exemplify prostate cancer as the cancer causing bone defect in the method of repairing a bone defect, said prior art clearly teaches a list of specific type of cancer that can caused the bone defect, including prostate cancer (see e.g., [0025]), and also teaches the bone graft composition comprises an active agent for treating the human disease or condition, e.g., prostate cancer (see claim 9). It would have been prima facie obvious to one of ordinary skilled in the art at the time of application was filed to selectively choose to locally administer the bone graft composite material of Margulies et al. that include naloxone hydrocholoride by implanting said material at the bone defect caused by prostate cancer, where the prostate cancer is localized or metastasized, for reducing volume of the prostate cancer tumor as the bone contains the prostate cancer, rendering the local implantation to the bone that contains the prostate cancer to be contacted by the bone graft composition. Please note the subject in need of repairing bone defect caused by prostate cancer is a subject in need of decreasing volume of a prostate cancer tumor according to page 22 of the instant specification that discloses the cancer includes a cancer that derives from a prostate cancer, e.g., metastases. One would have been motivated to do so, because Margulies teaches the bone graft composite material improves the bioavailability of agent contains therein, including naloxone hydrocholoride; Park et al. teaches prostate cancer can metastasizes to bone, and intraosseous injections that allow the implantation of tumor cells directly into a specific site of interest, such as the femur or tibia, can help study of the molecular pathways of advanced prostate cancer metastasis; and Bihari teaches naloxone is an opiate receptor A antagonist useful for treating prostate cancer, including reducing tumor size. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because Margulies et al. demonstrates the placement of the bone graft composition around the implant/polymethylmethacrylatebone cement construct adjacent to bone tissue, including tibia, of a subject; further teaches the bone defect is caused by cancer, including prostate cancer, the bone graft composition contains an active agent for treating the human disease or condition, including prostate cancer; and Bihari demonstrates opiate receptor A antagonist naltrexone successfully shrunk the tumor masses in patients with adenocarcinoma of the prostate, and teaches opiate receptor A antagonist can be naloxone or naltrexone. Accordingly, one would have reasonably expected that the naloxone hydrocholoride contains in the bone graft composite material/composition of Margulies et al. is a opiate receptor A antagonist useful for treating prostate cancer and reducing tumor volume; and therefore, by locally administering the bone graft composition of Margulies et al. by implanting to the bone defect caused by prostate cancer would have expected to repair said bone defect and treat cancer of the prostate by reducing tumor size. Please note the site of bone defect caused by prostate cancer tumor is a site where the prostate cancer tumor spreads to, and therefore, locally administering the bone graft composite material of Margulies by implanting to said site would necessarily introduce said material into the prostate cancer tumor.
In the alternative, according to MPEP 2145, II, “[t]he fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. Same logic is applicable to instant process claims, by practicing the method made obvious by the prior arts, one would have successfully decrease volume of a prostate cancer tumor.
Therefore, it would have been prima facie obvious to one of ordinary skilled in the art at the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on November 12, 2025 with respect to the rejection of claims 8, 11, 13-14 and 18 under 35 U.S.C. 103 as being unpatentable over Margulies et al. (US 2022/0016312 A1) in view of Park et al. (Methods Mol Biol., 2019. Vol. 1914: 295-308) and Bihari (US 6,384,044 B1; cited in non-final office action mailed on December 19, 2023) have been fully considered but they are not persuasive.
In Summary, applicants argues the claimed invention demonstrate unexpected results and would not have been expected based on the teachings of Margulies, Park and Bihari et al. by directing attention to the declaration under 37 CFR 1.132 filed on November 12, 2025.
In response, applicant’s presents the same arguments by quoting the declaration, which has already been addressed in the declaration section noted above. In short, based upon the declarant’s assertion that similar level of prostate cancer tumor volume reduction would have been expected for other formulations having a similar amount of naloxone as the formulation ZP001 of instant specification (see e.g., page 4, lists 7 in the declaration), the bone graft composition of Margulies et al. is a composition having a similar amount of naloxone, meeting the structural limitations in instant claims 8, 13 and 14, would expect to possess the same activity of decreasing volume of a prostate cancer tumor. Therefore, the fact that the method of applying, such as implanting, the bone graft composition of Margulies et al. at a therapeutically effective amount to the bone of a subject that contains prostate cancer would have been obvious to a person skilled in the art for treating the bone defect caused by prostate cancer (see rejection below), implanting similar product to the bone defect caused by said prostate cancer, where prostate cancer tumor is localized or metastasized, would naturally result in that property when the bone graft composition contacts with the prostate cancer tumor in the bone.
Additionally, as stated in the previous Final Office Action mailed on June 11, 2025, Applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention. According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
In Summary, the unexpected results applicant relies upon are demonstrated in Figure 4 of the specification, which includes results of the mouse xenograft studies disclosed on page 25-26 of the specification. According to page 25 of instant specification, mice were inoculated with PC3 prostate cancer cells into the bone marrow space of the tibia for 2 weeks, wherein half of the mice were implanted with a control (calcium phosphate based bone cement infused with 0.9% normal saline) and half were implanted with the ZP001, which is a composition with the ingredients as shown below:
PNG
media_image2.png
248
725
media_image2.png
Greyscale
(see e.g., p. 24, Example 1 of the instant specification).
In contrast, claim 8 broadly recites a method of decreasing volume of a prostate cancer tumor comprising locally administering by introduction into the prostate cancer of a subject in need thereof any therapeutically effective amount of a composition comprising from about 3.2 mg/mL to about 5.2 mg/mL of naloxone or a salt thereof, iron (III) sulfate, calcium phosphate, and collagen. The unexpected results exemplified in the specification specifically implant a single composition species (i.e., ZP001) that contains a specific amount of naloxone hydrochloride, iron (III) sulfate, calcium phosphate, and collagen as indicated above, and that does not provide adequate basis for concluding that similar results would be obtained for any other composition species administer at any therapeutically effective amount. Applicant only exemplify the composition ZP001 is implanted to a single subject species (mice) inoculated with prostate cancer cells PC3 inside the bone marrow space of the tibia, and said disclosure does not provide adequate basis for concluding that similar results would be obtained when said composition is locally introduced into prostate cancer tumor in a different way, including a different location and different local administration routes. The mouse xenograft studies of the specification do not exemplify any other composition species as broadly encompassed by instant claim 8. These finding demonstrates that applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention. The declaration under 37 CFR 1.132 filed on November 12, 2025 does not provide any evidence to support the unexpected results occur over the entire claimed range.
Again, as stated in the previous Final Office Action mailed on June 11, 2025, the mouse xenograft studies disclosed in the instant specification utilize an intraosseous injection method to implant tumor cells, in this case, PC3 prostate cancer cells, directly into a tibia as the site of interest is known in the art to be useful for studying bone metastatic progression in late-stage advanced prostate cancer patients according to Park et al. (Methods Mol Biol., 2019. Vol. 1914: 295-308) (see e.g., p. 2, 1st to 2nd paragraph; p. 6, “3.4 Intraosseous Injection (Intratibial or Intrafemoral)”). As such, based on the teachings of Margulies et al., Park et al., and Bihari as set forth in the rejection above, the unexpected results would have been expected, because one would have reasonably expected that locally administering the bone graft composite material of Margulies, which comprises naloxone hydrochloride as the active agent for treating prostate cancer as a human disease or condition, by implanting said material to the site of bone defect caused by prostate cancer would have successfully repair said bone defects by preventing bone destruction caused by prostate cancer, and treat prostate cancer by reducing tumor masses of said cancer, in the absence of evidence to the contrary.
Since applicant’s does not present any arguments and the declaration is insufficient to overcome the rejection under 35 U.S.C. 103 sets forth in the Office action, the rejection has been maintained for the same reasons of record and for the reasons set forth herein.
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 8, 11, 13-14 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 9 and 13 of U.S. Patent No. 12,310,962 B2 (reference patent) in view of Margulies et al. (US 2022/0016312 A1; cited in IDS filed on October 17, 2023), Park et al. (Methods Mol Biol., 2019. Vol. 1914: 295-308) and Bihari (US 6,384,044 B1; cited in non-final office action mailed on December 19, 2023).
The claims of the reference patent are drawn to a method of treating a tumor in a subject in need thereof, comprising locally administering to a site of the tumor in the subject a composition comprising an effective amount of an opioid growth factor receptor (OGFR) antagonist, wherein the OGFR antagonist is selected from the group consisting of naloxone, a salt of naloxone, naltrexone, a salt of naltrexone, and a combination thereof, and wherein the local administration of the composition reduces a volume of the tumor in the subject relative to an untreated subject, wherein the administering does not comprise administering an OGFR binding antagonist derived from the met5-enkephalin peptide.
Although the claims of the reference patent teaches reducing a volume of tumor and a composition comprising an effective amount of naloxone or a salt of naloxone for treating tumor and reducing a volume of the tumor, it does not teach a composition comprising from about 3.2 mg/ml to about 5.2 mg/ml of naloxone or salt thereof, iron (III) sulfate, calcium phosphate, and collagen; and does not teach prostate cancer. The claims of the reference patent also does not teach the composition as claimed in claims 13-14. The claims of the reference patent also does not teach a human being as claimed in claim 11. The claims of the reference patent also does not teach implanting as claimed in claim 18.
Margulies et al. teaches a bone graft composite material that can be applied to a bone defect caused by cancer for repairing the bone defect or facilitating repair or regeneration of bone in a human subject (see e.g., claims 8-9 and 11; [0170]; [0054]; [0061]). Margulies et al. further teaches the bone graft composition can be implanted, extruded, molded, or otherwise placed at the target repair site (see e.g., [0061]; [0175]); and the bone graft composition contains an active agent with therapeutic properties for treating disease and conditions in which it is desirable or necessary to promote bone growth either by stimulating bone formation or preventing bone destruction (see e.g., [0029]); wherein the active agent is an opioid growth factor receptor (OGFR) antagonist selected from the group consisting of naloxone, naltrexone, and a salt thereof (see e.g., [0013]); wherein the human disease or condition is a cancer, and the specific type of cancer include, inter alia, prostate cancer (see e.g., [0025]). Margulies et al. further teaches the bone graft composite is produced by mixing an appropriate diluent containing an active agent with a powder-dry slurry that is then administered directly and locally to a site of bone injury or surgical intervention where bone graft materials are normally placed to stimulate bone formation (see e.g., [0151]). Margulies et al. further teaches the dry slurry component of the bone graft material containing the following as a percentage of weight: 5% to 12% of iron (III) sulfate, 8% to 11% calcium phosphate dibasic, 9% to 12.5% calcium phosphate tribasic, 13% to 17% hydroxyapatite, 3% to 6% beta-tricalcium phosphate, 4% to 7.5% sodium phosphate dibasic, 11% to 15% sodium carbonate, 2% to 6% calcium oxide, 4% to 6% magnesium oxide, 0.5% to 2.5% L-ascorbic acid, and 18% to 23% powdered type-I collagen (see e.g., [0166]). Margulies et al. further teaches the diluent component of the bone graft material is a solution between 0.5 mL and 12.5 mL in volume composed of the following: 0.9% saline solution, 2% to 6% of acetic acid, 0.1% to 2% citric acid monohydrate, and 0.01% to 2% of naloxone hydrocholoride (see e.g., [0166]). Please note the bone graft composite material taught by Margulies et al. is a composition comprising a salt form of naloxone, iron (II) sulfate, calcium phosphate, and collagen. Margulies et al. further teaches the compositions and the materials are for bone grafting and repairing and/or filing a void or gap in a bone (see e.g., [0029]). Margulies et al. further teaches the bone graft composition has improved material properties and improved bioavailability of agents contained in the materials (see e.g., [0029]). Margulies et al. further teaches the target repair site can be, for example, a void, gap, or other defect in a bone or other bony structure in a body of a patient (see e.g., [0061]). Margulies et al. further teaches a working example that demonstrates the placement of the bone graft composition around the implant/polymethylmethacrylatebone cement construct adjacent to bone tissue, including tibia, after subjects undergo a resection of metastatic breast cancer tumor (see e.g., Working Example 5).
Park et al. teaches approximately 80% of advanced prostate cancer metastasizes to bone, yet the mechanisms of its selectiveness and growth in bone remain unclear (see e.g., p. 1, “Introduction” section, 1st paragraph). Park et al. further teaches a large number of animal models have been developed to aid in the study of the molecular pathways of advanced prostate cancer metastasis, including intraosseous injections that allow the implantation of tumor cells directly into a
specific site of interest, such as the femur or tibia (see e.g., p. 2, 1st to 2nd paragraph; p. 6, “3.4 Intraosseous Injection (Intratibial or Intrafemoral)”). Park et al. further teaches that since these tumors grow locally by design, the intraosseous injection is a very reliable and reproducible model to study the interaction between tumor cells and the bone marrow microenvironment, resulting in subsequent tumor growth (see e.g., p. 2, 2nd paragraph).
Bihari teaches a method of treating cancer of the prostate in a human male patient comprising administering an opiate receptor A antagonist that is naloxone or naltrexone (see e.g., claims 1-2; abstract); wherein said prostate to be treated has metastasized to other regions of the patient’s body than the prostate gland (see e.g., claim 6). Bihari et al. further teaches naloxone, has not generally proven to be effective when administered orally; it is available in a form suitable for injection and is better administered by injection (see e.g., Col. 6, line 56-58). Bihari further teaches the action of the compounds of the invention can be employed to terminate the rapid growth patterns of cancer and related abnormalities, and preventing tumor growth to continue, i.e., reducing the tumor burden (see e.g., Col. 2, line 34-48). Bihari further teaches this aspect of the invention is particularly significant in light of early diagnostic techniques which do reduce tumor size, or with procedures for tumor excision (see e.g., Col. 2, line 48-50). Bihari further teaches the patients with adenocarcinoma of the prostate and hard tumor mass during a digital rectal exam were immediately started on low-dose naltrexone, and after three months, the tumor masses has shrunk until they were no longer palpable by rectal examination (see e.g., Col. 8, line 19-40).
Please note the bone graft composite material of Margulies et al. is produced by mixing the dry slurry component with the diluent comprising 0.01% to 2% of naloxone hydrocholoride in a solution between 0.5 mL and 12.5 mL in volume (see e.g., [0166]). The actual amount of naloxone hydrocholoride can be calculated as follows:
0.01
%
→
0.01
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
0.1
m
g
/
m
L
2
%
→
2
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
20
m
g
/
m
L
, and that gives a range of 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Same logic is applicable to instant process claims, the bone graft composite material of Margulies et al. clearly comprises 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride, and that meets the structural limitations of “about 3.2 mg/mL to about 5.2 mg/mL of naloxone or salt thereof” of the claimed composition.
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of reference patent to selectively choose to incorporate the bone graft composite material of Margulies et al. as the composition comprising an effective amount of a salt of naloxone as the opioid growth factor receptor (OGFR) antagonist for treating prostate cancer tumor, because Margulies et al. teaches a bone graft composition comprising naloxone or salt thereof that can be locally administered to a site of bone injury caused by cancer, and said bone graft composition has improved material properties and bioavailability in addition to having therapeutic properties for treating disease and conditions, including prostate cancer; Park et al. teaches prostate cancer can metastasizes to bone, and implantation of tumor cells directly into a specific site of interest, such as the femur or tibia, can help study of the molecular pathways of advanced prostate cancer metastasis; and Bihari teaches naloxone is an opiate receptor A antagonist useful for treating prostate cancer, including reducing tumor size. One would have a reasonable expectation of success to arrive at the claimed invention, because the method of reference patent clearly teaches locally administrating a composition comprising an effective amount of naloxone or salt thereof to a site of tumor can treat tumor by reducing its volume, and Margulies et al. clearly demonstrate locally administration of bone graft composition, such as implanting, to site of bone injury caused by cancer; and Bihari demonstrates opiate receptor A antagonist naltrexone can successfully shrunk the tumor masses in patients with adenocarcinoma of the prostate, and teaches opiate receptor A antagonist can be naloxone or naltrexone. Accordingly, one would have reasonably expected that the naloxone hydrocholoride contains in the bone graft composite material/composition of Margulies et al. is a opiate receptor A antagonist useful for treating prostate cancer and reducing tumor volume in a subject, including human; and by substituting one composition comprising an effective amount of a salt of naloxone for another known composition containing the same, i.e., the bone graft composition taught by Margulies et al., for local administration, including implanting, would have expected to repair the bone defect caused by prostate cancer and treat tumor of the prostate cancer by reducing tumor size.
Claims 8, 11, 13-14 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10 and 12-13 of U.S. Patent No. 12,390,551 B2 (reference patent) in view of Margulies et al. (US 2022/0016312 A1; cited in IDS filed on October 17, 2023), Park et al. (Methods Mol Biol., 2019. Vol. 1914: 295-308) and Bihari (US 6,384,044 B1; cited in non-final office action mailed on December 19, 2023).
The claims of the reference patent are drawn to a method of treating a patient having prostate cancer, comprising identifying a bone defect in the patient caused by the cancer, locally administering at the site of the bone defect in the cancer patient in need thereof a composition consisting of a calcium phosphate, naloxone or a salt thereof, an iron excipient, an optional curing agent, and at least one of the following: an acidifying agent, collagen, and a diluent saline solution, wherein the composition provides a therapeutically effective amount of the iron excipient that increases mineral formation at the site of the bone defect, and wherein the iron excipient is iron (III) sulphate (see e.g., claim 1); wherein the calcium phosphate comprises biphasic calcium phosphate particles comprising about 20-60% hydroxyapatite and about 40-80% tricalcium phosphate (see e.g., claim 2-4).
Although the claims of the reference patent teaches a composition consisting of a calcium phosphate, naloxone or a salt thereof, an iron excipient, an optional curing agent, and at least one of the following: an acidifying agent, collagen, and a diluent saline solution for treating patient having prostate cancer, it does not teach a composition contains about 3.2 mg/ml to about 5.2 mg/ml of naloxone or salt thereof. The claims of the reference patent also does not teach the composition as claimed in claims 13-14. The claims of the reference patent also does not teach a human being as claimed in claim 11. The claims of the reference patent also does not teach implanting as claimed in claim 18.
Margulies et al. teaches a bone graft composite material that can be applied to a bone defect caused by cancer for repairing the bone defect or facilitating repair or regeneration of bone in a human subject (see e.g., claims 8-9 and 11; [0170]; [0054]; [0061]). Margulies et al. further teaches the bone graft composition can be implanted, extruded, molded, or otherwise placed at the target repair site (see e.g., [0061]; [0175]); and the bone graft composition contains an active agent with therapeutic properties for treating disease and conditions in which it is desirable or necessary to promote bone growth either by stimulating bone formation or preventing bone destruction (see e.g., [0029]); wherein the active agent is an opioid growth factor receptor (OGFR) antagonist selected from the group consisting of naloxone, naltrexone, and a salt thereof (see e.g., [0013]); wherein the human disease or condition is a cancer, and the specific type of cancer include, inter alia, prostate cancer (see e.g., [0025]). Margulies et al. further teaches the bone graft composite is produced by mixing an appropriate diluent containing an active agent with a powder-dry slurry that is then administered directly and locally to a site of bone injury or surgical intervention where bone graft materials are normally placed to stimulate bone formation (see e.g., [0151]). Margulies et al. further teaches the dry slurry component of the bone graft material containing the following as a percentage of weight: 5% to 12% of iron (III) sulfate, 8% to 11% calcium phosphate dibasic, 9% to 12.5% calcium phosphate tribasic, 13% to 17% hydroxyapatite, 3% to 6% beta-tricalcium phosphate, 4% to 7.5% sodium phosphate dibasic, 11% to 15% sodium carbonate, 2% to 6% calcium oxide, 4% to 6% magnesium oxide, 0.5% to 2.5% L-ascorbic acid, and 18% to 23% powdered type-I collagen (see e.g., [0166]). Margulies et al. further teaches the diluent component of the bone graft material is a solution between 0.5 mL and 12.5 mL in volume composed of the following: 0.9% saline solution, 2% to 6% of acetic acid, 0.1% to 2% citric acid monohydrate, and 0.01% to 2% of naloxone hydrocholoride (see e.g., [0166]). Please note the bone graft composite material taught by Margulies et al. is a composition comprising a salt form of naloxone, iron (II) sulfate, calcium phosphate, and collagen. Margulies et al. further teaches the compositions and the materials are for bone grafting and repairing and/or filing a void or gap in a bone (see e.g., [0029]). Margulies et al. further teaches the bone graft composition has improved material properties and improved bioavailability of agents contained in the materials (see e.g., [0029]). Margulies et al. further teaches the target repair site can be, for example, a void, gap, or other defect in a bone or other bony structure in a body of a patient (see e.g., [0061]). Margulies et al. further teaches a working example that demonstrates the placement of the bone graft composition around the implant/polymethylmethacrylatebone cement construct adjacent to bone tissue, including tibia, after subjects undergo a resection of metastatic breast cancer tumor (see e.g., Working Example 5).
Park et al. teaches approximately 80% of advanced prostate cancer metastasizes to bone, yet the mechanisms of its selectiveness and growth in bone remain unclear (see e.g., p. 1, “Introduction” section, 1st paragraph). Park et al. further teaches a large number of animal models have been developed to aid in the study of the molecular pathways of advanced prostate cancer metastasis, including intraosseous injections that allow the implantation of tumor cells directly into a
specific site of interest, such as the femur or tibia (see e.g., p. 2, 1st to 2nd paragraph; p. 6, “3.4 Intraosseous Injection (Intratibial or Intrafemoral)”). Park et al. further teaches that since these tumors grow locally by design, the intraosseous injection is a very reliable and reproducible model to study the interaction between tumor cells and the bone marrow microenvironment, resulting in subsequent tumor growth (see e.g., p. 2, 2nd paragraph).
Bihari teaches a method of treating cancer of the prostate in a human male patient comprising administering an opiate receptor A antagonist that is naloxone or naltrexone (see e.g., claims 1-2; abstract); wherein said prostate to be treated has metastasized to other regions of the patient’s body than the prostate gland (see e.g., claim 6). Bihari et al. further teaches naloxone, has not generally proven to be effective when administered orally; it is available in a form suitable for injection and is better administered by injection (see e.g., Col. 6, line 56-58). Bihari further teaches the action of the compounds of the invention can be employed to terminate the rapid growth patterns of cancer and related abnormalities, and preventing tumor growth to continue, i.e., reducing the tumor burden (see e.g., Col. 2, line 34-48). Bihari further teaches this aspect of the invention is particularly significant in light of early diagnostic techniques which do reduce tumor size, or with procedures for tumor excision (see e.g., Col. 2, line 48-50). Bihari further teaches the patients with adenocarcinoma of the prostate and hard tumor mass during a digital rectal exam were immediately started on low-dose naltrexone, and after three months, the tumor masses has shrunk until they were no longer palpable by rectal examination (see e.g., Col. 8, line 19-40).
Please note the bone graft composite material of Margulies et al. is produced by mixing the dry slurry component with the diluent comprising 0.01% to 2% of naloxone hydrocholoride in a solution between 0.5 mL and 12.5 mL in volume (see e.g., [0166]). The actual amount of naloxone hydrocholoride can be calculated as follows:
0.01
%
→
0.01
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
0.1
m
g
/
m
L
2
%
→
2
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
20
m
g
/
m
L
, and that gives a range of 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Same logic is applicable to instant process claims, the bone graft composite material of Margulies et al. clearly comprises 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride, and that meets the structural limitations of “about 3.2 mg/mL to about 5.2 mg/mL of naloxone or salt thereof” of the claimed composition.
In the present case, the bone graft composite material/composition taught by Margulies et al. renders obvious the composition instantly claimed. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of reference patent to selectively choose to incorporate the bone graft composite material of Margulies et al. as the composition consisting of a calcium phosphate, naloxone or a salt thereof, an iron excipient, an optional curing agent, and at least one of the following: an acidifying agent, collagen, and a diluent saline solution, because Margulies et al. teaches a bone graft composition comprising same ingredients that can be locally administered to a site of bone injury caused by cancer, including prostate cancer; Park et al. teaches prostate cancer can metastasizes to bone, and implantation of tumor cells directly into a specific site of interest, such as the femur or tibia, can help study of the molecular pathways of advanced prostate cancer metastasis; and Bihari teaches naloxone is an opiate receptor A antagonist useful for treating prostate cancer, including reducing tumor size. One would have a reasonable expectation of success to arrive at the claimed invention, because the method of reference patent clearly teaches locally administrating a composition comprising naloxone or salt thereof to a site of bone defect can treat prostate cancer, and Margulies et al. clearly demonstrate locally administration of bone graft composition, such as implanting, to site of bone injury caused by cancer; and Bihari demonstrates opiate receptor A antagonist naltrexone can successfully shrunk the tumor masses in patients with adenocarcinoma of the prostate, and teaches opiate receptor A antagonist can be naloxone or naltrexone. Accordingly, one would have reasonably expected that the naloxone hydrocholoride contains in the bone graft composite material/composition of Margulies et al. is a opiate receptor A antagonist useful for treating prostate cancer and reducing tumor volume in a subject, including human; and by substituting one composition (consisting of a calcium phosphate, naloxone or a salt thereof, an iron excipient, an optional curing agent, and at least one of the following: an acidifying agent, collagen, and a diluent saline solution) for another known composition containing the same, i.e., the bone graft composition taught by Margulies et al., for local administration, including implanting, would have expected to repair the bone defect caused by prostate cancer and treat tumor of the prostate cancer by reducing tumor size. Please note the site of bone defect caused by prostate cancer tumor is a site where the prostate cancer tumor spreads to, and therefore, locally administering the bone graft composite material of Margulies by implanting to said site would necessarily introduce said material into the prostate cancer tumor.
Claims 8, 11, 13-14 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 19/280,749 (reference application), in view of Margulies et al. (US 2022/0016312 A1; cited in IDS filed on October 17, 2023), Park et al. (Methods Mol Biol., 2019. Vol. 1914: 295-308) and Bihari (US 6,384,044 B1; cited in non-final office action mailed on December 19, 2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims recites a composition useful for treating cancer whereases the rejected claims cover methods of treating cancer. However, the specification of these patents and applications disclose the utility of the recited composition as covered by the instant methods of using the compounds, see Sun Pharmaceutical Industries, Ltd., v. Eli Lilly and Co. where the district court ruled that the claims of the ‘826 patent were invalid in light of the ‘614 patent which disclosed gemcitabine’s use in cancer treatment, but did not claim it. In making this ruling, the district court relied on the Federal Circuit’s earlier rulings on double patenting of compound claims, mainly Geneva Pharmaceuticals, Inc, v. GlaxoSmithKline PLC, 349 F. 3d 1373 (Fed. Cir. 2003), and Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353 (Fed. Cir. 2008). In both of these cases, the Federal Circuit found claims of a later patent invalid for obviousness-type double patenting where an earlier patent claimed a compound, disclosing its utility in the specification, and a later patent claimed a method of using the compound for a use described in the specification of the earlier patent. The cases also established that in determining the scope of compound claims for a double patenting rejection one must look to the specification to interpret the utility of the compound.
In the alternative, one of ordinary skill in the art would have look into Margulies et al. that teaches a bone graft composite material that can be applied to a bone defect caused by cancer for repairing the bone defect or facilitating repair or regeneration of bone in a human subject (see e.g., claims 8-9 and 11; [0170]; [0054]; [0061]). Margulies et al. further teaches the bone graft composition can be implanted, extruded, molded, or otherwise placed at the target repair site (see e.g., [0061]; [0175]); and the bone graft composition contains an active agent with therapeutic properties for treating disease and conditions in which it is desirable or necessary to promote bone growth either by stimulating bone formation or preventing bone destruction (see e.g., [0029]); wherein the active agent is an opioid growth factor receptor (OGFR) antagonist selected from the group consisting of naloxone, naltrexone, and a salt thereof (see e.g., [0013]); wherein the human disease or condition is a cancer, and the specific type of cancer include, inter alia, prostate cancer (see e.g., [0025]). Margulies et al. further teaches the bone graft composite is produced by mixing an appropriate diluent containing an active agent with a powder-dry slurry that is then administered directly and locally to a site of bone injury or surgical intervention where bone graft materials are normally placed to stimulate bone formation (see e.g., [0151]). Margulies et al. further teaches the dry slurry component of the bone graft material containing the following as a percentage of weight: 5% to 12% of iron (III) sulfate, 8% to 11% calcium phosphate dibasic, 9% to 12.5% calcium phosphate tribasic, 13% to 17% hydroxyapatite, 3% to 6% beta-tricalcium phosphate, 4% to 7.5% sodium phosphate dibasic, 11% to 15% sodium carbonate, 2% to 6% calcium oxide, 4% to 6% magnesium oxide, 0.5% to 2.5% L-ascorbic acid, and 18% to 23% powdered type-I collagen (see e.g., [0166]). Margulies et al. further teaches the diluent component of the bone graft material is a solution between 0.5 mL and 12.5 mL in volume composed of the following: 0.9% saline solution, 2% to 6% of acetic acid, 0.1% to 2% citric acid monohydrate, and 0.01% to 2% of naloxone hydrocholoride (see e.g., [0166]). Please note the bone graft composite material taught by Margulies et al. is a composition comprising a salt form of naloxone, iron (II) sulfate, calcium phosphate, and collagen. Margulies et al. further teaches the compositions and the materials are for bone grafting and repairing and/or filing a void or gap in a bone (see e.g., [0029]). Margulies et al. further teaches the bone graft composition has improved material properties and improved bioavailability of agents contained in the materials (see e.g., [0029]). Margulies et al. further teaches the target repair site can be, for example, a void, gap, or other defect in a bone or other bony structure in a body of a patient (see e.g., [0061]). Margulies et al. further teaches a working example that demonstrates the placement of the bone graft composition around the implant/polymethylmethacrylatebone cement construct adjacent to bone tissue, including tibia, after subjects undergo a resection of metastatic breast cancer tumor (see e.g., Working Example 5). Please note the bone graft composite material of Margulies et al. is produced by mixing the dry slurry component with the diluent comprising 0.01% to 2% of naloxone hydrocholoride in a solution between 0.5 mL and 12.5 mL in volume (see e.g., [0166]). The actual amount of naloxone hydrocholoride can be calculated as follows:
0.01
%
→
0.01
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
0.1
m
g
/
m
L
2
%
→
2
g
100
m
L
×
1000
m
g
1
g
=
x
m
g
1
m
L
,
x
=
20
m
g
/
m
L
, and that gives a range of 0.1 mg/mL to 20 mg/mL of naloxone hydrochloride.
Park et al. teaches approximately 80% of advanced prostate cancer metastasizes to bone, yet the mechanisms of its selectiveness and growth in bone remain unclear (see e.g., p. 1, “Introduction” section, 1st paragraph). Park et al. further teaches a large number of animal models have been developed to aid in the study of the molecular pathways of advanced prostate cancer metastasis, including intraosseous injections that allow the implantation of tumor cells directly into a
specific site of interest, such as the femur or tibia (see e.g., p. 2, 1st to 2nd paragraph; p. 6, “3.4 Intraosseous Injection (Intratibial or Intrafemoral)”). Park et al. further teaches that since these tumors grow locally by design, the intraosseous injection is a very reliable and reproducible model to study the interaction between tumor cells and the bone marrow microenvironment, resulting in subsequent tumor growth (see e.g., p. 2, 2nd paragraph).
Bihari teaches a method of treating cancer of the prostate in a human male patient comprising administering an opiate receptor A antagonist that is naloxone or naltrexone (see e.g., claims 1-2; abstract); wherein said prostate to be treated has metastasized to other regions of the patient’s body than the prostate gland (see e.g., claim 6). Bihari et al. further teaches naloxone, has not generally proven to be effective when administered orally; it is available in a form suitable for injection and is better administered by injection (see e.g., Col. 6, line 56-58). Bihari further teaches the action of the compounds of the invention can be employed to terminate the rapid growth patterns of cancer and related abnormalities, and preventing tumor growth to continue, i.e., reducing the tumor burden (see e.g., Col. 2, line 34-48). Bihari further teaches this aspect of the invention is particularly significant in light of early diagnostic techniques which do reduce tumor size, or with procedures for tumor excision (see e.g., Col. 2, line 48-50). Bihari further teaches the patients with adenocarcinoma of the prostate and hard tumor mass during a digital rectal exam were immediately started on low-dose naltrexone, and after three months, the tumor masses has shrunk until they were no longer palpable by rectal examination (see e.g., Col. 8, line 19-40).
In other words, it would have been prima facie obvious to one of ordinary skill in the art to modify the composition of reference application in view of the teachings of Margulies et al. to selectively choose to incorporate percentage range, amount, and ingredient species taught by the bone graft composition of Margulies et al. in order to arrive at a composition species useful for treating prostate cancer tumor, because Margulies et al. teaches the bone graft composition comprising same ingredients that can be locally administered to a site of bone injury caused by cancer, including prostate cancer; Park et al. teaches prostate cancer can metastasizes to bone, and implantation of tumor cells directly into a specific site of interest, such as the femur or tibia, can help study of the molecular pathways of advanced prostate cancer metastasis; and Bihari teaches naloxone is an opiate receptor A antagonist useful for treating prostate cancer, including reducing tumor size. One would have a reasonable expectation of success to arrive at the claimed invention, because Margulies et al. clearly demonstrate locally administration of bone graft composition, such as implanting, to site of bone injury caused by cancer; and Bihari demonstrates opiate receptor A antagonist naltrexone can successfully shrunk the tumor masses in patients with adenocarcinoma of the prostate, and teaches opiate receptor A antagonist can be naloxone or naltrexone. Accordingly, one would have reasonably expected that the naloxone hydrocholoride contains in the bone graft composite material/composition of Margulies et al. is a opiate receptor A antagonist useful for treating prostate cancer and reducing tumor volume in a subject, including human; and by modifying one composition containing the same ingredient using the amount of known composition containing the same, i.e., the bone graft composition taught by Margulies et al., for local administration, including implanting, would have expected to repair the bone defect caused by prostate cancer and treat tumor of the prostate cancer by reducing tumor size. Please note the site of bone defect caused by prostate cancer tumor is a site where the prostate cancer tumor spreads to, and therefore, locally administering the bone graft composite material of Margulies by implanting to said site would necessarily introduce said material into the prostate cancer tumor.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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