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 .
Priority
This application was filed on and is a U.S. national Stage application under 35 U.S.C. 371 of International Patent Application No. 371 of PCT/CN2022/125935 filed 10/18/2022, which claims the benefit of the priority of China Patent Application No. 202111215700.9 filed 10/19/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements submitted 04/19/2024, 01/06/2025, 04/11/2025, and 08/27/2025 have been considered by the examiner.
Claim Status
Claims 1, 4-6, 9-13, 15-17, 20-21, 25, 28, 31-32, 34-35 are being examined on the merits in this office action.
Claim Objections
Claim 17 is objected to for the following minor informality: claim 17 contains the acronym “PSMA and TRPV6 receptor”, and an acronym in the first instance of claims should be expanded upon/spelled out with the acronym indicated in parentheses, i.e., prostate-specific membrane antigen (PSMA) and Transient Receptor Potential Vanilloid 6 (TRPV6). The abbreviations can be used thereafter.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 34-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a pharmaceutical preparation comprising a ligand-drug conjugate and the pharmaceutically acceptable excipients, does not reasonably provide enablement for a compound used to prevent and treat all forms of cancers including blood and brain cancers, immune diseases, metabolic diseases, neurological diseases and cardiovascular diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1561 (Fed. Cir., 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558,1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary
2) the amount of direction or guidance provided
3) the presence or absence of working examples
4) the nature of the invention
5) the state of the art
6) the relative skill of those in the art
7) the predictability of the art
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099,1108,427 F.2d 833, 839,166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims and the nature of the invention
The invention is drawn to a method of treating and preventing cancer, immune diseases, cardiovascular, metabolic or neurological diseases and the diseases include all the cancers recited in claim 35, heart attack, obesity, coma, head injury, Alzheimer’s disease, Parkinson’s disease etc.
Cancer is a broad term and encompasses cancers occurring in various hard and soft tissues. The main categories include: Carcinoma (cancers that begin in the skin or tissues that line or cover organs), Sarcoma (Cancers in bone, cartilage, muscles or connective tissues), Leukemia (Cancers that form in the blood forming tissues), Lymphoma and myeloma (Cancers that begin in the immune system) and Central nervous system cancer (cancers of the brain or spinal cord). The claims of the instant application do not limit the cancer being treated, prevented or suppressed to any particular type of cancer, for example lung cancer or breast cancer.
Additionally, neurodegenerative disorders cover an immense array of largely unrelated disorders that have different modes of action and different origins. The term covers such diverse disorders as Alzheimer's Disease; Parkinson's Disease; ALS and variants such as forms of ALS-PDC; dementia of the frontal lobe type (DFT), Tourette's syndrome; multiple systems atrophy (MSA; once called Shy-Drager syndrome), certain spinal muscular atrophies, such as Werdnig-Hoffmann and Wohlfart-Kugelberg-Welander. Other diseases include those of the neuroacanthocytosis family, such as McLeod syndrome (MLS), Huntington disease–like2 (HDL2) and epilepsy (FAPED), and prion diseases (Cedars Sinai). Other neurological disorders include multiple sclerosis, pain disorders, and headaches such as migraines, stroke, brain tumors neurovascular, epilepsy and seizures, encephalitis, myasthenia gravis, meningitis (Cedar Sinai and Johns Hopkins medicine). As indicated above, the breadth of neurological disorders is extremely broad, and the list above is not exhaustive. The claims of the instant application do not limit the neurological disorders being treated.
Additionally, the list of metabolic disorders is broad and includes diseases such as diabetes, Gaucher’s disease, and hemochromatosis etc.
Secondly, the term “preventing” is a potent and absolute term indicating that the method of prevention will necessarily prevent the onset of any cancer, regardless of the cause and in every instance by the administration of the claimed peptide ligand.
Since the instant specification does not provide a limiting definition of the term “preventing”, the term has been interpreted expansively. The term “preventing” encompasses a wide range of situations, from preventing a disease from occurring to preventing it from progressing, and in addition, the term is not limited by any time frame.
The applicant is claiming a “method of preventing” in claim 34-35. Prevention, as defined by Merriam-Webster dictionary, is to keep from happening or existing, which implies taking advance measure against something possible or probable. In addition, preventing embraces complete 100% inhibition. Therefore, the evidence of 100% prevention would be more challenging to obtain than the evidence of treatment since one would have to show that the administration of the conjugate would never develop any cancer, neurological disease, metabolic or immune or cardiovascular disease. The instant specification is bereft of evidence of prevention of any cancer, neurological disease, metabolic or immune or cardiovascular disease. The specification does not demonstrate the efficacy of the claimed conjugate or any known conjugate in the treatment or prevention of any cancer, neurological disease, metabolic or immune or cardiovascular diseases.
Since absolute success in preventing cancer, neurological disease, metabolic or immune or cardiovascular diseases is not reasonably possible based on the state of the art at the earliest effective filing date of the instant application, the specification, which lacks an objective showing that cancer or the recited conditions can be prevented, is viewed as lacking.
The claims are thus broad insofar as to suggest that the claimed conjugate can treat and prevent all cancers, neurological diseases, metabolic or immune or cardiovascular diseases.
The state of the prior art and the level of predictability in the art and the relative skill of those in the art
The state of the art is such that there is evidence and established literature on the many types of cancers (National Cancer Institute-https://www.cancer.gov/about-cancer/understanding/what-is-cancer (NCI), page 6, paragraph 1) and each cancer has its own causative factor and different cellular behaviors (National Cancer Institute, https://www.cancer.gov/about-cancer/causes-prevention/patient-prevention-overview-pdq (NCI2) page 2 and 3). Examples of numerous forms of cancers include Breast cancer, uterine corpus endometrial carcinoma, Bladder Urothelial carcinoma, Lung cancer, cervical cancer, pancreatic cancer, Prostate cancer, ovarian cancer, Blood cancer or Brain and nervous system cancers. These are further subdivided to include carcinomas like Basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma and Adenocarcinoma. There are also other forms of malignant melanoma, cylindroma, germ cell tumors and many more. Treatment of cancer is complex and usually takes into consideration the type of cancer including location, its stage and genetic characteristics. Therefore, treatment for one type of cancer, may not be useful in treating other types of cancers (Merck Manual - Cancer treatment Principles By Robert Gale, page 1, paragraph 1 and 2).
Given that there is no evidence in the art of a compound that has been found to generally treat all cancers, the treatment of cancer generally is not considered enabled. Most cancer drugs are known to be effective against a limited or closely related cancers (Merck Manual - Cancer therapy, By Robert Gale, page 1, and paragraph 1, 2). Therefore, a compound that is effective against cancer generally would be an exception and more proof of the claimed invention would be required. Merck teaches the median 5-year survival rates of various types of cancer as shown below (Merck - cancer therapy, page 3).
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Medical News Today (https://www.medicalnewstoday.com/articles/322700 - By Christina Chun) teaches that a 5- year survival rate does not indicate whether or not treatment has removed all signs of cancer, but is useful for comparing relative severity of different types of cancer (Medical News Today, Page 1, paragraph 8). One of ordinary skill in the art would not be able to use the claimed invention to treat cancer generally and achieve a reasonable level of success in doing so due to the absence in the art of a compound that is able to treat cancer generally. It is well established that a utility rejection is therefore proper when the scope of enablement is not reasonably correlated to the scope of the claim.
The state of the art is such that there is evidence and established literature on the many types of neurological disorders and each has its own causative factor and different cellular behaviors. The most common types of neurological disorders included in the Global Burden of Disease (GBD) Study–Alzheimer’s and other dementias, Parkinson’s disease, multiple sclerosis, epilepsy, and headache disorders (migraine, tension-type headache [TTH], and medication-overuse headache [MOH])–represent 3 percent of the worldwide burden of disease (Kiran et al. p. 1-2). Migraine and epilepsy represent one-third and one-fourth of this neurological burden, respectively, and dementia and Parkinson’s disease are among the top 15 conditions with the most substantial increase in burden in the past decade. In 2010, neurological disorders constituted 5.5 percent of years lived with disability (YLDs), or 42.9 million YLDs; migraine, epilepsy, and dementia were among the top 25 causes of YLDs. Migraine leads the list of neurological disorders, representing more than 50 percent of neurological YLDs or 2.9 percent of global YLDs; epilepsy represents 1.1 percent of global YLDs (Kiran et al.). The treatment of neurological disorders is complex given how diverse the disorders are as well as their diverse etiology. In addition, given that there is no evidence in the art of a compound that has been found to generally treat all neurological disorders, the treatment of neurological disorders generally is not considered enabled.
Additionally, there is no evidence in the art for a compound that can treat and prevent all the conditions claimed such as preventing head injury, preventing cancers or Alzheimer’s disease.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.”
The instant disclosure is focused on a composition that comprises a ligand-drug conjugate and pharmaceutical excipients and a method for treating and preventing cancers, neurological diseases, metabolic or immune or cardiovascular diseases.
With regards to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] ... anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved” and physiological activity is generally considered to be an unpredictable factor.
See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.).
As a result, the specification needs to have more details on how to make and use the invention to be enabling. The relative skill of those in the art is high. However, the treatment and prevention of cancers, neurological diseases, metabolic or immune or cardiovascular diseases is highly unpredictable.
The examiner cites Huang et al. (WO2020156513A1 – hereinafter “Huang”) as evidentiary references to illustrate the state of the art.
Huang teaches ligand-drug conjugates and pharmaceutical composition comprising the conjugate. Huang teaches the composition comprising the conjugate was effective in inhibiting lung cancer tumor cells expansion (See Fig. 4-8). Huang does not teach that conjugate was effective in treating and preventing cancers, neurological diseases, metabolic or immune or cardiovascular diseases.
The teachings show how unpredictable the treatment of cancer is, especially in the case of a compound that is used to prevent and treat cancer in general. Considering the state of the prior art, it is apparent that the instantly claimed conjugate is not capable of use to treat and prevent all cancers, neurological diseases, metabolic or immune or cardiovascular diseases.
The amount of direction or guidance provided and the presence or absence of working examples
The claims are drawn to a composition that comprises a ligand-drug conjugate and pharmaceutical excipients and a method for treating and preventing cancers, neurological diseases, metabolic or immune or cardiovascular diseases.
The instant specification does not include any examples showing effect of the claimed conjugate in treating and preventing cancers, neurological diseases, metabolic or immune or cardiovascular diseases.
The quantity of experimentation necessary
Given the well-known unpredictability of the art as well the incomplete experimental evidence commensurate in scope with the claims, the skilled artisan would not be able to agree that the claimed conjugate can treat and prevent any and all cancers, neurological diseases, metabolic or immune or cardiovascular diseases. In order to determine if the claimed peptide ligand would treat any of the claimed diseases and conditions, suitable dosage as well as clinical trials or assays that can correlate to clinical efficacy of such treatment would be needed. This is undue experimentation given the limited guidance and experimentation provided by the applicant.
In view of the Wands factors discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in unduly burdensome experimentation to assess whether administration of the claimed conjugate would be successful in treating and preventing cancers, neurological diseases, metabolic or immune or cardiovascular diseases. Thus, the rejection of these claims under 35 USC 112(a) is proper.
Claims 1, 4-6, 9-13, 15-17, 20-21, 25, 28, 31-32, 34-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2137 states that "the written description requirement for a genus must be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
For written description, the analysis (a) considers actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties, functional characteristics when coupled with known or disclosed and (d) representative number of examples.
Brief Statement of the Issue(s)
The claims recite a pharmaceutical preparation comprising an active drug comprising a ligand-drug conjugate and a pharmaceutically acceptable adjuvant. Examiner notes that claim 1 recites any and every ligand-drug conjugate which optionally comprises a pharmaceutically acceptable adjuvant. The claims further recite a method including treating and preventing a genus of cancers, immune, cardiovascular, metabolic or neurological diseases by administering the ligand-drug conjugate of claim 1.
Claim Scope
Claim 1 is representative of the pending claims scope and recites any and every ligand-drug conjugate which optionally comprises a pharmaceutically acceptable adjuvant. The ligand-drug conjugate is administered to a subject to treat and prevent a genus of diseases and conditions including cancers, immune, cardiovascular, metabolic or neurological diseases. The claimed method thus encompasses a genus of ligand-drug conjugates to treat numerous diseases and conditions. It is unclear if the claimed ligand-drug conjugate encompasses all and every ligand-drug conjugate and if the claimed methods encompass trillions of species of treating numerous diseases, via all forms of administration (e.g., topical, anal, oral, intramuscular, intravenous, etc.), or if the claimed methods include only one or two treatable diseases in a limited patient population and via limited routes of administration. Accordingly, the claim scope appears to be vast and highly varied.
Actual reduction to practice and disclosure of drawings or structural chemical formulas
The instant claims recite that the ligand-drug conjugate is a dual ligand-drug conjugate and that optionally, the ligand-drug conjugate has the structure as recited in claim 17. The instant application has only reduced to practice one compound which is the compound CR19213 and is the structure as recited as an option in claim 17.
The instant application provides no data on the effect of the compound in treating and preventing cancers, immune, cardiovascular, metabolic or neurological diseases.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. In this case, the claims encompass a genus of ligand-drug conjugates and a genus of diseases and conditions as recited in the claims, but zero embodiments of the claimed methods were actually reduced to practice wherein a specific cancer or disease was treated in a subject at any disclosed dosage at all.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of zero species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of zero examples of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Zero disclosure of the specific ligand-drug conjugate. Additionally, the structure of the compound recited in claim 17 is recited as an option. Additionally, there is zero disclosure of what constitutes “treating” or “preventing” or “enhancing an immune effector cell response” or “reducing immunosuppression” of any of the broad diseases and conditions. At best, the instant specification provides vague and generic guidance regarding what the invention hopes to achieve (See [0042—0043 of Spec. filed 04/19/2024); however, such disclosures fail to meaningfully inform artisans of any usable and specific dosage formulations or dosage ranges that would be capable of satisfying the limitations of the claimed methods.
Additionally, there is zero disclosure of any examples showing the effect of a specific ligand-drug conjugate in treating and preventing a representative number of species of the recited diseases. Further, there is zero disclosure regarding what the successful outcome of a “treating” or “preventing” for any particular species of “cancers, immune, cardiovascular, metabolic or neurological diseases” is provided on record. The disclosure does not meaningfully relate to a structure/function relationship such that one of ordinary skill in the art is meaningfully made aware of the specific ligand-drug conjugate, and the exact dosages of the specific compound are “effective” to any extent in the treatment and prevention of any disease. The closest data of record lacks a clear nexus with the claimed invention, and it is prima facie unclear if the claimed compounds have a reasonable expectation of successfully treating and preventing all the cancers immune, cardiovascular, metabolic or neurological diseases recited in the claims. Accordingly, basic identifying characteristics pertinent to the claimed genus are left unanswered, including “which compounds can actually treat or prevent any particular species of disorder?”, “what concentration of compound is ‘effective’ for any particular species of disorder?”, “what exact outcome constitutes a successful ‘treatment’ or prevention?
Thus, the specification fails to provide adequate written description for the genus of compounds and diseases claimed and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim Interpretation
The instant claims recite the article “optionally”. Examiner is interpreting the limitations after "optionally" as entirely optional and not a required limitation.
Claims 1, 4, 6, 9, 11-13, 15-17, 20-21, 25, 34-35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huang et al. (WO2020156513A1 – hereinafter “Huang”).
Regarding claim 1, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient).
Regarding claim 4, Huang teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent) [0254].
Regarding claims 6 and 9, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes buffering agent such as citric acid buffer (which reads on pH regulator) [0254].
Regarding claims 11-13, Huang teaches wherein the pharmaceutically acceptable carrier includes mannitol (which reads on freeze dried excipient and is a known polyol), and that the carrier includes glucose, which is a saccharide [0257].
Regarding claim 15-16, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient). Huang teaches the composition with pH of 6.8, 7.2 [0284, 0307, 0310, 0313, 0340].
Regarding claim 17, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the conjugate is a dual-ligand drug conjugate (Title; [0001]), targeting PSMA (FOLR1) and TRPV6 (claim 12-15; [0025-0027, 0146, 0165, 0269]).
Regarding claim 20-21, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient) and that the conjugate is freeze-dried [0284, 0307, 0310]. Huang teaches preparations comprising mixtures of the conjugate compound mixed with the one or more pharmaceutically acceptable carriers [0257-0260]. Huang teaches that the composition with pH of 6.8, 7.2 [0284, 0307, 0310, 0313, 0340].
Regarding claim 25, Huang teaches freeze-drying the conjugate compound [0284, 0307, 0310].
Regarding claim 34-35, Huang teaches method for treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a conjugate compound, wherein the disease is selected from the group consisting of cancer, immune diseases, cardiovascular diseases, metabolic diseases, and neurological diseases, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer, kidney cancer, leukemia, ovarian cancer, gastric cancer, uterine cancer, endometrial cancer, liver cancer, colon cancer, thyroid cancer, pancreatic cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, lymphoma, and multiple myeloma, wherein the immune disease is an autoimmune disease, wherein the autoimmune disease is selected from the group consisting of connective tissue disease, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus (claims 38-46; [0004-0006, 0077-0086]).
Claims 1, 4-6, 9-13, 15-17, 20-21, 25, 28, 31-32, 34-35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by White et al. (WO2016004043A1 – hereinafter “White”).
Regarding claim 1, White teaches a conjugate of a targeting moiety and an active agent [0006], wherein the conjugates include a targeting ligand and an active agent connected by a linker [0008-0010], and White further teaches pharmaceutical formulations are provided containing the conjugates or particles containing the conjugates described herein, or pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable vehicle [0034], wherein the formulation is at a pH of 7.4 phosphate-buffered formulation, or pH 6.2 citrate-buffered formulation; formulations for lyophilization such as pH 6.2 citrate-buffered formulation with 3% mannitol, pH 6.2 citrate-buffered formulation with 4% mannitol, 1 % sucrose [00334-00339, 00354-00357, 00467, 00503], that the formulation can be freeze-dried [00278, 00463, 00503], and that the composition can be prepared with water [0054, 00286]. Examiner notes that the citrate buffer reads on pH regulator, water reads on a solvent, and mannitol reads on a freeze-dried excipient.
Regarding claim 4, White teaches a conjugate of a targeting moiety and an active agent [0006], wherein the conjugates include a targeting ligand and an active agent connected by a linker [0008-0010], and White further teaches pharmaceutical formulations are provided containing the conjugates or particles containing the conjugates described herein, or pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable vehicle [0034], and that the composition can be prepared with water [0054, 00286].
Regarding claim 5, White teaches a conjugate of a targeting moiety and an active agent [0006], wherein the conjugates include a targeting ligand and an active agent connected by a linker [0008-0010], and wherein the concentration is from 0.1-100 mg/ml [00347].
Regarding claims 6, 9-10, White teaches wherein the formulation is at a pH of 7.4 phosphate-buffered formulation, or pH 6.2 citrate-buffered formulation; formulations for lyophilization such as pH 6.2 citrate-buffered formulation with 3% mannitol, pH 6.2 citrate-buffered formulation with 4% mannitol, 1 % sucrose [00334-00339, 00354-00357, 00467, 00503]. Examiner notes that the sodium citrate or citric acid on [00339] reads on the pH regulator comprising buffer salt.
Regarding claims 11-13, White teaches a conjugate of a targeting moiety and an active agent [0006], wherein the conjugates include a targeting ligand and an active agent connected by a linker [0008-0010], and White further teaches pharmaceutical formulations are provided containing the conjugates or particles containing the conjugates described herein, or pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable vehicle [0034], wherein the formulation is at a pH of 7.4 phosphate-buffered formulation, or pH 6.2 citrate-buffered formulation; formulations for lyophilization such as pH 6.2 citrate-buffered formulation with 3% mannitol, pH 6.2 citrate-buffered formulation with 4% mannitol, 1 % sucrose [00334-00339, 00354-00357, 00467, 00503], that the formulation can be freeze-dried [00278, 00463, 00503]. Examiner notes that mannitol is an example of a polyol and sucrose is an example of saccharide and further 4% mannitol is equivalent to 40 mg/ml and 4% mannitol, 1 % sucrose is a ratio of 1:4, thus anticipating claims 11-13.
Regarding claim 15-16, White teaches a conjugate of a targeting moiety and an active agent [0006], wherein the conjugates include a targeting ligand and an active agent connected by a linker [0008-0010], and White further teaches pharmaceutical formulations are provided containing the conjugates or particles containing the conjugates described herein, or pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable vehicle [0034], wherein the formulation is at a pH of 7.4 phosphate-buffered formulation, or pH 6.2 citrate-buffered formulation; formulations for lyophilization such as pH 6.2 citrate-buffered formulation [00334-00339, 00354-00357, 00467, 00503], that the formulation can be freeze-dried [00278, 00463, 00503], and that the composition can be prepared with water [0054, 00286]. Examiner notes that the citrate buffer reads on pH regulator, water reads on a solvent, and mannitol reads on a freeze-dried excipient.
Regarding claims 17, 20-21, White teaches a conjugate of a targeting moiety and an active agent [0006], wherein the conjugates include a targeting ligand and an active agent connected by a linker [0008-0010], and White further teaches pharmaceutical formulations are provided containing the conjugates or particles containing the conjugates described herein, or pharmaceutically acceptable salts thereof, in a pharmaceutically acceptable vehicle [0034], wherein the formulation is at a pH of 7.4 phosphate-buffered formulation, or pH 6.2 citrate-buffered formulation; formulations for lyophilization such as pH 6.2 citrate-buffered formulation with 3% mannitol, pH 6.2 citrate-buffered formulation with 4% mannitol, 1 % sucrose [00334-00339, 00354-00357, 00467, 00503], that the formulation can be freeze-dried [00278, 00463, 00503], and that the composition can be prepared with water [0054, 00286]. Examiner notes that the citrate buffer reads on pH regulator, water reads on a solvent, and mannitol reads on a freeze-dried excipient. White teaches a method of preparation wherein the conjugate is prepared by dissolving the conjugate with water and mix with the one or more pharmaceutically acceptable excipients such as pH modifying agents [00458, 00479, 00627].
Regarding claims 25 and 28, White teaches that that the formulation can be freeze-dried [00278, 00463, 00503], and that the composition can be prepared with water [0054, 00286], that solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use [00481], with a pH of 6.2 [00334-00339, 00354-00357, 00467, 00503].
Regarding claims 31-32, White teaches devices that comprise the formulation for subcutaneously, or intramuscularly administration [00561-00562] and that the formulation can be used for injection [00338-00339, 00520, 00562].
Regarding claims 34-35, White teaches a method of treating a subject in need thereof comprising administering a therapeutically effective amount of the formulation, wherein the subject has cancer or inflammation, wherein the cancer is lymphoma (e.g., non-Hodgkin's lymphoma), renal cell carcinoma, prostate cancer, ovarian cancer, breast cancer, colorectal cancer, neuroendocrine cancer, endometrial cancer, pancreatic cancer leukemia, lung cancer, glioblastoma multforme, stomach cancer, liver cancer, sarcoma, bladder cancer (claims 44-46; [0007, 0036, 0056, 00186-00188]).
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.
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Claims 1, 4-6, 9, 11-13, 15-17, 20-21, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55-72 of copending Application No. 17/426,293. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims recite a conjugate compound or a pharmaceutically acceptable salt thereof, such as CB-20B (claim 55), and pharmaceutical composition comprising the conjugate compound and pharmaceutically acceptable carrier (claim 56).
The instant claims recite a pharmaceutical preparation, comprising an active drug and optionally a pharmaceutically acceptable adjuvant, wherein the active drug comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable adjuvant comprises one or more of a freeze-dried excipient, a pH regulator, and a solvent (claim 1), wherein the conjugate is a dual ligand-drug conjugate, and optionally has the structure recite in claim 17 (claim 17).
The difference between the copending claims and the instant claims is that the copending claims do not recite the specific pharmaceutically acceptable carrier. The instant carriers are known to be included in compositions comprising the conjugate as disclosed by Huang et al. (WO2020156513A1 – hereinafter “Huang”).
Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of the copending application and include the specific pharmaceutically acceptable carriers as taught by Huang, since Huang teaches the same conjugate in a composition including carriers such as mannitol and buffer salt. One of ordinary skill in the art would have had a reasonable expectation of success in using the carriers of Huang in a composition comprising the conjugate to prepare a freeze-dried composition that is stable. The copending claims render obvious the instant claims.
Regarding claim 4, Huang teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent) [0254]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 5, Huang teaches concentrations including 0.01 to 10mg/kg [0265]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claims 6 and 9, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes buffering agent such as citric acid buffer (which reads on pH regulator) [0254]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claims 11-13, Huang teaches wherein the pharmaceutically acceptable carrier includes mannitol (which reads on freeze dried excipient and is a known polyol), and that the carrier includes glucose, which is a saccharide [0257]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 15-16, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient). Huang teaches that the composition with pH of 6.8, 7.2 [0284, 0307, 0310, 0313, 0340]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 17, the copending claims recite the compound of the structure CB-20B (claims 55-72), which is identical to the instant structure.
Regarding claim 20-21, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient) and that the conjugate is freeze-dried [0284, 0307, 0310]. Huang teaches preparations comprising mixtures of the conjugate compound mixed with the one or more pharmaceutically acceptable carriers [0257-0260]. Huang teaches that the composition with pH of 6.8, 7.2 [0284, 0307, 0310, 0313, 0340]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 25, Huang teaches freeze-drying the conjugate compound [0284, 0307, 0310]. It would have been obvious to modify the copending claims with the teachings of Huang.
Claims 1, 4-6, 9, 11-13, 15-17, 20-21, 25, 34-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/757,487. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims recite a conjugate compound or a pharmaceutically acceptable salt thereof, comprising a first and second targeting molecule and pharmaceutical composition comprising the conjugate and pharmaceutically acceptable carrier (claims 1-16).
The instant claims recite a pharmaceutical preparation, comprising an active drug and optionally a pharmaceutically acceptable adjuvant, wherein the active drug comprises a ligand-drug conjugate or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable adjuvant comprises one or more of a freeze-dried excipient, a pH regulator, and a solvent (claim 1), wherein the conjugate is a dual ligand-drug conjugate, and optionally has the structure recite in claim 17 (claim 17).
The difference between the copending claims and the instant claims is that the copending claims do not recite the specific pharmaceutically acceptable carrier. The instant carriers are known to be included in compositions comprising the conjugate as disclosed by Huang et al. (WO2020156513A1 – hereinafter “Huang”).
Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of the copending application and include the specific pharmaceutically acceptable carriers as taught by Huang, since Huang teaches the same conjugate in a composition including carriers such as mannitol and buffer salt. One of ordinary skill in the art would have had a reasonable expectation of success in using the carriers of Huang in a composition comprising the conjugate to prepare a freeze-dried composition that is stable. The copending claims render obvious the instant claims.
Regarding claim 4, Huang teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent) [0254]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 5, Huang teaches concentrations including 0.01 to 10mg/kg [0265]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claims 6 and 9, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes buffering agent such as citric acid buffer (which reads on pH regulator) [0254]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claims 11-13, Huang teaches wherein the pharmaceutically acceptable carrier includes mannitol (which reads on freeze dried excipient and is a known polyol), and that the carrier includes glucose, which is a saccharide [0257]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 15-16, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient). Huang teaches that composition with pH of 6.8, 7.2 [0284, 0307, 0310, 0313, 0340]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 17, the copending claims recite a conjugate compound or a pharmaceutically acceptable salt thereof, comprising a first and second targeting molecule and pharmaceutical composition comprising the conjugate and pharmaceutically acceptable carrier and structures that read on the instant claims (claims 1-16)
Regarding claim 20-21, Huang teaches a conjugate compound or a pharmaceutically acceptable salt thereof [0009], and further teaches a pharmaceutical composition that comprises the conjugate compound in the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier [0074], wherein the pharmaceutically acceptable carrier includes sterile water (which reads on a solvent), buffering agent such as citric acid buffer (which reads on pH regulator) [0254], and mannitol [0257] (which reads on freeze dried excipient) and that the conjugate is freeze-dried [0284, 0307, 0310]. Huang teaches preparations comprising mixtures of the conjugate compound mixed with the one or more pharmaceutically acceptable carriers [0257-0260]. Huang teaches that the composition with pH of 6.8, 7.2 [0284, 0307, 0310, 0313, 0340]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claim 25, Huang teaches freeze-drying the conjugate compound [0284, 0307, 0310]. It would have been obvious to modify the copending claims with the teachings of Huang.
Regarding claims 34-35, the copending claims recite a method for treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate compound or the pharmaceutically acceptable salt thereof (claim 17-18), wherein the disease is selected from the group consisting of a cancer, an immunological disease, a cardiovascular disease, a metabolic disease, and a neurological disease (claims 19-20).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
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/MERCY H SABILA/Examiner, Art Unit 1654
/TARA L MARTINEZ/Primary Examiner, Art Unit 1654
Prosecution Insights