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 . 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.
Priority
The instant application is a 371 of PCT/EP2021/067239 filed on 06/23/2021 and claims foreign priority to PCT/EP2020/071045 filed on 07/24/2020 and NL2025904 filed on 06/24/2020. The certified copies of the foreign priority applications filed on 12/23/2022 are acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/23/2023 and 06/18/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 11/22/2023 is acknowledged. Claims 1-32 are cancelled. Claims 33-52 are newly added.
Accordingly, claims 33-52 are pending and being examined on the merits herein.
Claim Objections
Claim 37 is objected to because of the following informalities: The alternative options (b) and (c) recited in claim 37 appear to be duplicates.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 39-43 and 49 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 39 recites the limitation "the carboxyl group of the glucuronic acid moiety of A1”. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference of a “A1”.
Claim 40 recites the limitation “the saponin derivative corresponds to the saponin represented by Molecule 1”. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference of a “saponin represented by Molecule 1”. Claims 41 and 42 depend from claim 40 but do not overcome the described indefinite issue.
Claim 42 recites the limitation "the carboxyl group of the glucuronic acid moiety of A1”. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference of a “A1”.
Claim 43 recites the limitation “A2 is …, or A2 is …”. There is insufficient antecedent basis for this limitation in the claim because there is no prior reference of a “A2”.
Claim 49 recites “… wherein when the aldehyde group in the aglycone core structure is derivatized by transformation into a hydrazone bond through reaction with … the glucuronic acid is derivatized, and wherein when the saponin is QS-21 and the carboxyl group of the glucuronic acid moiety of QS-21 is derivatized by reaction of … the aldehyde group is also modified.”.
Claim 49 is indefinite because it is not clear if the limitation after the recited “when” is further limiting the structure of the saponin derivative or merely an intended use.
For purposes of examination, claims 39-43 are presumed to be dependent from claim 38.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 38 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 38 recites “a saponin derivative of the quillaic acid saponin represented by Molecule 1 …”. The recited Molecule 1 structure does not show an aldehyde group on the aglycone core structure of the saponin derivative being derivatized as required in claim 33. Therefore, claim 38 fails to include all of the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 51-52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease, does not reasonably provide enablement for preventing a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease. 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.
To be enabling, the specification of the patent 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:
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 the 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 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) The breadth of the claims,
2) The nature of the invention,
3) The state of the prior art,
4) The level of one of ordinary skill,
5) The level of predictability in the art,
6) The amount of direction provided by the inventor,
7) The existence of working examples, and
8) The quantity of experimentation necessary
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 nature of the invention, the breadth of the claims, and relative skill level
The invention relates to a method of treating or preventing a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition of claim 33 to the subject.
The claims are broad in that they encompass the prevention of a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease. Instant claim 51 recites “A method of preventing … cancer … auto-immune disease…”.
In the absence of an explicit definition in Applicant’s specification, the claims are given their broadest reasonable interpretation (See MPEP 2111). Institute for International Medical Education (IIME, reference included with PTO-892), defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (see page 16, “Prevention”). IIME further states that “Primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe. Secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health. Tertiary prevention consists of the measures available to reduce or eliminate long-term”.
Therefore, in order to give the broadest reasonable interpretation to the claims, “prevention” or "prevent" are thus interpreted to mean that the onset of a condition never occurs and the patient’s health is protected and preserved.
The relative skill of those in the art is high, that of an MD or PHD, someone with experience in the recited diseases.
The amount of direction or guidance provided and the presence or absence of working examples
Applicant demonstrates in Examples 2 and 3 that chemically modified SO1861 and QS21 were co-administered with a ligan toxin fusion, or an antibody-protein toxin conjugate, resulting in enhanced cell killing activity of target-expressing cells (see pages 110-119 in instant specification). Applicant shows in Table A5 and A6 on pages 116-119 that the cytoxoicity, hemolytic activity, and endosomal escape activity were enhanced for the co-administered antibody or ligand toxin conjugates.
The instant disclosure does not identify a method that could be used by one of ordinary skill in the art to determine that a subject would have predictably developed a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease without the claimed methods in order to establish that such the recited diseases was prevented.
The described example suggests that the recited saponin compounds were effective in enhancing the activity of various conjugates. However, the example does not demonstrate prevention of the recited diseases or a predictable method to identify patients who would have developed the recited diseases.
The state and predictability of the art
There are no art recognized methods that could be used to establish that a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease was prevented using therapeutic treatment or to identify patients who would predictably develop the recited diseases in order to predictably identify that prevention was achieved using therapeutic approaches. Rather, the art indicates that the recited diseases were not predictable.
Lewndowska et al. (in PTO-892) teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors had been identified that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that can contribute to the formation of cancer are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer would have developed in order to establish that it was prevented.
Galbadage et al. (in PTO-892) discloses there are differences in the propagation of COVID-19 (an infectious disease and viral infection) among select nations. Galbadage et al. discloses that this raises questions on whether a full scientific understanding of disease transmission modes has yet to be attained, and thus whether there are more effective ways to prevent its spread (see page 1, second paragraph). Galbadage et al. discloses there are no current cures or vaccines for SARS-CoV-2 (see page 3 right column), and further illustrates in Figure 1 (page 2) the different potential modes of transmission of COVID-19.
The teachings of Galbadage demonstrates that prevention of an infectious disease and/or viral infection such as coronavirus is not predictable due to an incomplete understanding in how this infection spreads and thus difficulties to develop more effective methods to prevent transmission. Therefore, the preventative application against an infectious disease and/or viral infection using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed an infectious disease and/or viral infection and, therefore, there is no predictable way to determine that infectious disease and/or viral infection was prevented using the claimed method.
Sniderman et al. (in PTO-892) discloses that severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels (see Abstract). Sniderman et al. discloses that the most common cause is autosomal dominant hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor, apolipoprotein B (APOB), or proprotein convertase subtilisin kexin type 9 (PCSK9) genes. However, Sniderman et al. discloses that many subjects with severe inherited hypercholesterolemia have no defects in these genes, and that these cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects (see Abstract). Sniderman et al. discloses that a polygenic origin for hypercholesterolemia is likely in many cases, and therefore genetic screening strategies are not easily endorsable as they pose great challenges to comprehensive, effective, and economical implementation (see right column page 1935).
The teachings of Sniderman et al. demonstrates that prevention of hypercholesterolemia is not predictable due to potential unknown gene mutations or consequences of polygenic, epigenetic, or acquired defects that are not identifiable through genetic screenings. Therefore, the preventative application against a hypercholesterolemia using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed a hypercholesterolemia and, therefore, there is no predictable way to determine that a hypercholesterolemia was prevented using the claimed method.
Bhasin et al. (in PTO-892) discloses that hyperoxaluria continues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management (see Abstract). Bhasin et al. discloses that definitive diagnosis of primary hyperoxaluria (PH) is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis (see Abstract). Bhasin discloses several genetic and biochemical basis of this disease, (page 237), and diagnosis involves a combination of clinical, radiological, biochemical, histopathological and genetic studies in primary hyperoxaluria (see right column page 238 to left column page 239). Bhasin et al. discloses that precise diagnosis is of paramount importance for prognostic and treatment implications and also for prenatal screening in appropriate cases where PH is suspected (see right column page 238).
The teachings of Bhasin et al. demonstrates that prevention of hyperoxaluria is not predictable due to involved diagnosis methods needed to identify the hyperoxaluria in a patient and to further determine the appropriate treatment. Therefore, the preventative application against a hyperoxaluria using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed a hyperoxaluria and, therefore, there is no predictable way to determine that a hyperoxaluria was prevented using the claimed method.
Bowen et al. (in PTO-892) discloses large mutational heterogeneity in the coagulation factor VIII gene in haemophilia A and the coagulation factor IX gene in haemophilia B, making the collection of informative genetic data for familial investigations a difficult task (see left column page 1). Bowen et al. discloses that insights gained from the molecular pathology of these diseases have revealed both subtle and major complexity at the genetic and protein levels (see right column page 13), and that insights gained from polymorphisms and their ethnic variants hint at a complex evolution awaiting further exploration (see right column page 13).
The teachings of Bowen et al. demonstrates that prevention of haemophilia A and haemophilia B is not predictable due to large mutational heterogeneity as well as the complexities from polymorphisms in the molecular pathology of these diseases. Therefore, the preventative application against a haemophilia A and haemophilia B using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed a haemophilia A and haemophilia B and, therefore, there is no predictable way to determine that a haemophilia A and haemophilia B was prevented using the claimed method.
Fairbanks et al. (in PTO-892) discloses that alpha 1-antitrypsin deficiency is an inherited metabolic disorder that predisposes the affected individual to chronic pulmonary disease, in addition to chronic liver disease, cirrhosis, and hepatocellular carcinoma (see Abstract). Fairbanks et al. discloses that the clinical presentation of liver disease is variable, and the genetic and environmental factors that predispose some individuals to liver disease while sparing others are unknown, and that the mechanisms of liver and lung disease are distinct and unique (see Abstract).
The teachings of Fairbanks et al. demonstrates that prevention of alpha 1-antitrypsin is not predictable due to variability in the clinical presentation of this disease and unknown genetic and environmental factors that predispose individuals to this disease. Therefore, the preventative application against alpha 1-antitrypsin using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed alpha 1-antitrypsin and, therefore, there is no predictable way to determine that alpha 1-antitrypsin was prevented using the claimed method.
Bonkovsky et al. (in PTO-892) discloses that acute hepatic porphyrias are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms (see Abstract). Bonkovsky et al. discloses that diagnoses for these diseases are often missed or delayed because the clinical symptoms mimic other more common disorders (see Abstract).
The teachings of Bonkovsky et al. demonstrates that prevention of acute hepatic porphyrias is not predictable due to clinical symptoms for these diseases mimicking other more common disorders and leading to missed and/or delayed diagnoses. Therefore, the preventative application against acute hepatic porphyrias using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed acute hepatic porphyrias and, therefore, there is no predictable way to determine that acute hepatic porphyrias was prevented using the claimed method.
Aldinc et al. (in PTO-892) discloses that transthyretin‑mediated (ATTR) amyloidosis is a heterogeneous, multisystem disease in which a significant proportion of patients develop a mixed phenotype of polyneuropathy (PN) and cardiomyopathy (see left column page 2). Aldinc et al. discloses that diagnosis of transthyretin‑mediated (ATTR) amyloidosis is often difficult or delayed due to the heterogenous, non-specific nature of ATTR amyloidosis and symtpoms overlapping with other diseases (see left column page 2).
The teachings of Aldinc et al. demonstrates that prevention of transthyretin-mediated amyloidosis is not predictable due to clinical symptoms for these diseases overlapping with other diseases and leading to missed and/or delayed diagnoses. Therefore, the preventative application against transthyretin-mediated amyloidosis using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed transthyretin-mediated amyloidosis and, therefore, there is no predictable way to determine that transthyretin-mediated amyloidosis was prevented using the claimed method.
Roep et al. (in PTO-892) discloses the problems and promises of research into human immunology and autoimmune disease (see Abstract). Roep et al. discloses that translational research in autoimmunity is hampered by a number of hurdles, including a lack of knowledge regarding initiating and pathologically relevant autoantigens, the low frequency of autoreactive pathogenic B and T cells, difficulty in accessing the affected tissue, differences between self-reactive and pathogen-specific lymphocytes, a lack of etiologically relevant preclinical animal models and the heterogeneity of disease presentation (see Abstract). Roep et al. discloses that there is inability to predict the likelihood of success of therapies in humans using animal models (see right column page 48).
The teachings of Roep et al. demonstrates that prevention of autoimmune disease is not predictable due to a lack of knowledge regarding initiating and pathologically relevant autoantigens, the low frequency of autoreactive pathogenic B and T cells, difficulty in accessing the affected tissue, differences between self-reactive and pathogen-specific lymphocytes, a lack of etiologically relevant preclinical animal models and the heterogeneity of disease presentation. Therefore, the preventative application against autoimmune disease using the recited composition is highly unpredictable in the arts because there was no art recognized method of determining whether a patient would predictably have developed autoimmune disease and, therefore, there is no predictable way to determine that an autoimmune disease was prevented using the claimed method.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of a predictable method to identify patients who would develop a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease without treatment, one of ordinary skilled in the art would not be able to predictably use the claimed agent to prevent the recited diseases. Furthermore, the quantity of experimentation to develop a method that could be used to prevent a cancer, an infectious disease, viral infection, hypercholesterolemia, primary hyperoxaluria, haemophilia A, haemophilia B, alpha-1 antitrypsin related liver disease, acute hepatic porphyria, transthyretin-mediated amyloidosis, or an auto- immune disease would be undue because a method to predictably identify a patient who would get the recited diseases does not exist and as described above, one of ordinary skill would have to further develop this method such that the recited method could then be used as a preventative measure against the recited diseases. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 33-42, 44-48, and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Ragupathi et al. (Expert Review of Vaccines, 2014 in IDS filed 11/22/2023) in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892), Marciani et al. (US5977081A in IDS filed 11/22/2023), and Fernandez-Tejada et al. (Acc Chem Res., 2016 in IDS filed 11/22/2023).
Ragupathi et al. discloses QS-21, a triterpene glycoside purified from Quillaja Saponaria (QS), as a uniquely potent immunological adjuvant (see Abstract). Ragupathi et al. discloses that QS-21 possesses adjuvant properties for a range of antigens, and has an ability to augment clinically significant antibody and T-cell responses to vaccine antigens against a variety of infectious diseases, degenerative disorders, and cancers (see Abstract). Ragupathi et al. discloses that QS-21 provides a robust method to induce increased immune responsiveness and decreased toxicity (see Abstract). Ragupathi et al. discloses the molecular structure of QS-21 shown in Figure 1 and below:
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Here, the QS-21 compound of Ragupathi et al. is the same base saponin derivative with the same aglycone core structure and first / second saccharide chains recited in the instant claims. Ragupathi et al. discloses that the amphipathic nature of QS-21 makes it an ideal adjuvant for mixing with most large protein antigens or conjugate vaccines where adjuvant and antigen are likely to stay in close proximity where injected (Depot effect) until incorporated into antigen-presenting cells (APCs) (see bottom left column page 464). Ragupathi et al. discloses that unconjugated carbohydrate or peptide antigens on the other hand may require administration with aluminum salts, liposomes, ISCOMs, and among other adjuvant formulations conferring a depot effect or facilitating uptake of antigen and adjuvant by APCs (see bottom left column to top right column page 464).
The difference between Ragupathi and the claimed invention is that Ragupathi et al. does not disclose the aldehyde group of the aglycone core structure being derivatized by hydrazone formation with a hydrazide, or imine formation with an amine, or chemoselective reversible oxime formation with a hydroxylamine.
Qi et al. discloses conjugation of beta-glucan with hydrazone and disulfide linkers to improve the immunogenicity of Zika Virus E protein (see Abstract). Qi et al. discloses that E proteins are an ideal antigen for vaccine development, but have poor immunogenicity, which necessitates a formulation with adjuvants (see Abstract). Qu et al. discloses that the antigenic epitopes of the antigen may be shielded by the macromolecular adjuvant, which in turn, the immunomodulatory sites of the adjuvant may be shielded by the bulky antigen. Moreover, Qi et al. discloses that the conjugate may elicit the undesired immune response to the adjuvant, which is harmful for vaccine development. Thus, Qu et al. proposes conjugation with beta-glucan to overcome these disadvantages and improve the immunogenicity via acidic-labile hydrazone linkers between the E protein and beta-glucan to sufficiently detach the two components in the immune cells (see Abstract). Qi et al. discloses that acid-labile hydrazone bonds have been utilized for nanoparticle-targeted anticancer drugs, in which low pH values of endosomes (pH 5.5–6.0) and lysosomes (pH 4.5–5.0) rendered rapid cargo release after hydrolysis of pH-sensitive hydrazone bonds in the micelle (see left column page 1934). Qi et al. discloses the structures of four conjugates that were prepared in Figure 11 and shown below:
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Here, the conjugate “E-PS-2” (top right conjugate) is a EMCH linker and meets the limitations of the hydrazide linker recited in the instant claims, and the conjugate “E-PS-1” (top left conjugate) is an AEM linker and meets the limitations of transformation into an amide bond through reaction with AEM recited in the instant claims.
Marciani et al. discloses novel triterpene saponin analogs having adjuvant and immunostimulatory activity (see Abstract). Marciani et al. discloses that their novel compounds contain a lipophilic moiety covalently attached to a carboxyl group present on the 3-O-glucoronic acid of the triterpene saponin (see Abstract). Marciani et al. discloses that the attachment of the lipophile moiety yields a saponin derivative that is easier to purify, potentially less toxic, chemically more stable, and with equal or better adjuvant properties than the original saponins (see Abstract). Marciani et al. provides a Formula II structure which represents their conjugated saponin-lipophilic compounds shown below:
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Here, the circled portion highlights the conjugation of the lipophilic moiety to a saponin compound. X is S, O, NH or a linking group and R3 is a residue of a lipophilic molecule. This conjugated location is the same derivatized location as recited in the instant claims for the carboxyl group of a glucuronic acid moiety as recited in instant claim 37 as well as seen in compound 32 in instant claim 45. Marciani et al. discloses that the lipophilic moiety can be attached to the saponins via a linking group (see column 8 lines 50-53). Marciani et al. discloses that the linking group can be one or more bifunctional linkers that covalently attach the carboxylic acid group of the 3-O glucuronic acid moiety of the triterpene core to a suitable functional group present on the lipophilic molecule (see column 8, lines 50-59). Marciani et al. discloses that non-limiting examples of linker groups include alkylene diamines (NH-CH), NH), where n is from 2 to 12; aminoalcohols (HO-(CH)-NH), where r is from 2 to 12, and amino acids that are optionally carboxy-protected; ethylene and polyethylene glycols (H-(O-CH-CH-)-OH, where n is 1-4 aminomercaptains and mercaptocarboxylic acids (see column 9 lines 60-67). Marciani et al. discloses other suitable heterobifunctional cross-linkers such as sulfosuccinimidyl 4-(N-maleimidocyclohexane)-1-carboxylate (see column 14, lines 44-57) and also discloses using suitable reagents to form an amide or ester linakge to a lipophilic moiety (see column 11 lines 22-30). Marciani et al. discloses pharmaceutical compositions comprising their saponin-lipophile conjugate and one or more pharmaceutically acceptable diluents, carriers, or excipients (see column 6, lines 7-12). Marciani et al. discloses that their saponin conjugates can be administered to enhance the immune response against antigens produced by the use of DNA vaccines (see column 23, lines 40-45). Marciani et al. discloses that typical vaccines used in this approach include viral vaccines (influenzas, herpes, and others), cancer vaccines, and parasitic vaccines (see column 23, lines 40-52).
Fernandez-Tejada et al. discloses the development of improved vaccine adjuvants based on the saponin natural product QS-21 through chemical synthesis (see section “Conspectus”). Fernandez-Tejada et al. discloses various modifications to the QS-21 compound including modifications to the triterpene C4-aldehyde substituent (see section “Conspectus”). Fernandez-Tejada et al. shows in Figure 13 the modification of C4-aldehyde and C16-hydroxlygroups groups on various saponin triterpene domains as shown below:
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Here, the circled “R1” group corresponds to the same C4 aldehyde group that is derivatized on the aglycone core structure of the saponin recited in the instant claims. Fernandez-Tejada et al. discloses that the C4-aldehyde was previously proposed to be important for activity based on the reduced adjuvant activity of QS-21 derivatives in which this aldehyde is replaced with an amine (see left column page 1751). However, Fernandez-Tejada et al. discloses that compounds such as variant 73 and 74, which lack this C4-aldehyde group, exhibited similar or higher antibody titers in mouse vaccinations (see last paragraph left column page 1751). Therefore, Fernandez-Tejada et al. concludes that this aldehyde group is dispensable (see last paragraph left column page 1751 through first paragraph left column page 1752), which further suggests that this position can be derivatized without affecting the adjuvant properties of the saponin compounds.
It would have been prima facie obvious to combine Ragupathi et al. with Qi, Marciani et al., and Fernandez-Tejada et al. before the effective filing date of the claimed invention by modifying the C4-aldehyde position of the QS-21 shown in Ragupathi with an EMCH linker to form saponin-antigen conjugates as suggested by the teachings of Qi, Marciani, and Fernandez-Tejada to arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because Ragupathi et al. establishes the use of QS-21 as an adjuvant for various antigens, and Qi et al. provides guidance of using an EMCH linker to form similar carbohydrate-based adjuvant-antigen conjugates to improve the immunogenicity of the antigen. Therefore, an ordinary skilled artisan would have been motivated to conjugate the QS-21 of Ragupathi to an antigen using the EMCH linker disclosed in Qi et al. in order to gain the advantage of improved immunogenicity and better targeted delivery of the saponin conjugates to antigen presenting cells (APCs). Furthermore, Marciani et al. provides guidance of modifying and forming lipophilic-saponin conjugates using a linker at the carboxylic acid group of the 3-O glucuronic acid, and Fernandez-Tejada suggests modification of the C4-aldehyde position on the aglycone core structure of saponins while retaining the same or better adjuvant properties of saponins. Therefore, an ordinary skilled artisan could also have chosen from a finite number of identified, predictable solutions of forming saponin conjugates via a linker as disclosed in Marciani and alternative modification sites such as the C4-aldehyde position disclosed in Fernandez-Tejada in order to attach the EMCH linker of Qi and form the modified antigen-saponin conjugate as suggested by the combined teachings of Ragupathi and Qi.
In regards to instant claims 37 and 42, it would have also been prima facie obvious to further attach a lipophilic moiety using the AEM linker disclosed in Qi et al. at the carboxylic acid group of the 3-O glucuronic acid in the modified antigen-saponin conjugate as suggested by the combined teachings of Ragupathi, Qi, Marciani, and Fernandez-Tejada. One of ordinary skill in the art would have would made this further modification with a reasonable expectation of success because Marciani et al. provides guidance to conjugate a lipophilic moiety at the carboxylic acid group of the 3-O glucuronic acid on a saponin compound via a linking group, and provides further guidance that the lipophilic moiety can be conjugated using bifunctional linkers. Additionally, Qi et al. provides guidance of using an AEM linker for similar carbohydrate-based adjuvant conjugates. Therefore, an ordinary skilled artisan could have chosen from a finite number of identified, predictable solutions of alternative bifunctional linkers such as the AEM linker disclosed in Qi et al. to attach the lipophilic moiety, and would be further motivated to do so in order to form saponin conjugates that are easier to purify, potentially less toxic, chemically more stable, and with equal or better adjuvant properties than the original saponins as disclosed in Marciani.
In regards to instant claim 51, it would have also been prima facie obvious to administer an effective amount of the modified lipophilic moiety-saponin conjugate as suggested by the combined teachings of Ragupathi, Marciani, Fernandez-Tejada, and Qi to treat a cancer, an infectious disease, or a viral infection as suggested in Ragupathi and Marciani to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because both Ragupathi and Marciani disclose saponin and saponin derivative compounds as having a significant adjuvant effect for various vaccines including cancers, infectious diseases, or viral infections.
Claim (s) 49 is rejected under 35 U.S.C. 103 as being unpatentable over Ragupathi et al. (Expert Review of Vaccines, 2014 in IDS filed 11/22/2023) in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892), Marciani et al. (US5977081A in IDS filed 11/22/2023), and Fernandez-Tejada et al. (Acc Chem Res., 2016 in IDS filed 11/22/2023), as applied to claim 33, and further in view of Wang et al. (J. Med. Chem, 2019 in PTO-892).
The combined teachings of Ragupathi, Qi, Marciani, and Fernandez-Tejada teach the pharmaceutical composition of claim 33 as described above.
The difference between the combined teachings of Ragupathi, Qi, Marciani, and Fernandez-Tejada and the instant invention is that the combined teachings of Ragupathi, Qi, Marciani, and Fernandez-Tejada do not teach wherein the carboxyl group of the glucuronic acid moiety of QS-21 is derivatized by reaction of (HATU).
Wang et al. discloses the synthesis of QS-17/18 analogues (see Abstract). Wang et al. discloses the structure of their saponin compound 7 shown below:
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Here, the circled functional group is the same position as the carboxyl group of the glucuronic acid moiety of a QS-21 as recited in the instant claims, and the primary modification feature to the QS compound. Wang et al. discloses that the synthesis of compound 7 involves a reaction with HATU for amide bond formation (see Scheme 5 on page 1672). Wang et al. discloses that compound 7 can be a structurally defined alternative to GPI-0100 and may also provide a valuable clue for rational design of new QS-based vaccine adjuvants with better adjuvant properties (see Abstract).
It would have been prima facie obvious to combine Ragupathi, Qi, Marciani, and Fernandez-Tejada with Wang et al before the effective filing date of the claimed invention by using the attachment chemistry involving reaction with HATU as disclosed in Wang on the carboxyl group of the glucuronic acid moiety to attach an lipophilic moiety on the modified antigen saponin conjugate as suggested by the combined teachings of Ragupathi, Qi, Marciani, and Fernandez-Tejada described above to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Wang et al. provides guidance of modifying this glucuronic acid moiety location using HATU to attach a functional group via amide bond linkage, and Marciani et al. discloses the attachment of a similar lipophilic moiety via amide bond formation on the carboxyl group of the glucuronic acid moiety of saponin compounds. Therefore, an ordinary skilled artisan could have chosen from a finite number of identified, predictable solutions of amide bond formation chemistries such as the HATU chemistry disclosed in Wang et al. to attach the lipophilic moiety to the modified antigen-saponin conjugate as suggested by the combined teachings of Ragupathi, Qi, Marciani, and Fernandez-Tejada described above.
Claim (s) 33, 40, 43, and 51-52 are rejected under 35 U.S.C. 103 as being unpatentable over Bhargava et al. (Mol. Onco., 2017 in IDS filed 11/22/2023) in view of Qi et al. (Molecular Pharmaceutics, published 04/29/2020 in PTO-892), Marciani et al. (US5977081A in IDS filed 11/22/2023), and Fernandez-Tejada et al. (Acc Chem Res., 2016 in IDS filed 11/22/2023).
Bhargava discloses the co-administration of dianthin-EGF with the glycosylated triterpene SO1861 for the treatment of pancreatic carcinoma (see Abstract and left column page 1529). Here, the SO1861 compound of Bhargava meets the limitation of the base saponin derivative in the recited claims as well the recited saccharide sequence in instant claim 43 because as evidenced in the instant specification, SO1861 contains the recited A2 saccharide sequence (see Table A1 on page 90 in instant specification). Furthermore, the dianthin-EGF meets the limitation of a receptor-ligand – toxin conjugate because the dianthin is a known plant toxin (see left column page 1529), and the attached EGF is a known receptor ligand that targets EGFR (see left column page 1533). Bhargava et al. discloses that in vitro investigations with the pancreatic carcinoma cell lines BxPC-3 and MIA PaCa-2 revealed no significant differences to off-target cells in the half maximal inhibitory concentration (IC50) for the fusion protein (see Abstract). However, Bhargava et al. discloses that combination with SO1861 decreased the IC50 for BxPC-3 cells from 100 to 0.17 nm, whereas control cells remained unaffected. Bhargava et al. also discloses that monotherapy of BxPC-3 xenografts in CD-1 nude mice led to a 51.7% average reduction in tumor size (40.8 mm3) when compared to placebo; however, combined treatment with SO1861 resulted in a more than 13-fold better efficacy (3.0 mm3 average tumor size) with complete regression in 80% of cases (see Abstract). Bhargava et al. discloses that at the effective concentration, there were no observed liver toxicity and saw no other side effects with the exception of a reversible skin hardening at the SO1861 injection site, alongside an increase in platelet counts, plateletcrit, and platelet distribution width (see Abstract). Bhargava et al. concludes that combining a targeted toxin (dianthin-EGF) with SO1861 is proven to be a very promising approach for pancreatic cancer treatment (see Abstract).
The difference between Bhargava and the claimed invention is that Bhargava et al. does not teach the aldehyde group of the aglycone core structure being derivatized by hydrazone formation with a hydrazide, or imine formation with an amine, or chemoselective reversible oxime formation with a hydroxylamine.
The independent teachings of Qi, Marciani, and Fernandez-Tejada are as described above.
It would have been prima facie obvious to combine Bhargava with Qi, Marciani, and Fernandez-Tejada before the effective filing date of the claimed invention by attaching the dianthin-EGF to the SO1861 at the C4-aldehyde position using an EMCH linker as suggested by the teachings of Qi, Marciani, and Fernadez-Tejada to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Bhargava et al. establishes the use of SO1861 as an adjuvant for the dianthin-EGF antigen, and Qi et al. provides guidance of using an EMCH linker to form similar carbohydrate-based adjuvant-antigen conjugates to improve the immunogenicity. Therefore, an ordinary skilled artisan would have been motivated to conjugate the SO1861 to dianthin-EGF of Bhargava by using the EMCH linker disclosed in Qi et al. in order to gain the advantage of improved immunogenicity and better targeted delivery of the saponin conjugates to the tumor cells. Furthermore, Marciani et al. provides guidance of modifying and forming lipophilic-saponin conjugates using a linker at the carboxylic acid group of the 3-O glucuronic acid, and Fernandez-Tejada suggests modification of the C4-aldehyde position on the aglycone core structure of saponins while retaining the same or better adjuvant properties of saponins. Therefore, an ordinary skilled artisan could also have chosen from a finite number of identified, predictable solutions of forming saponin conjugates via a linker as disclosed in Marciani and alternative modification sites such as the C4-aldehyde position disclosed in Fernandez-Tejada in order to attach the EMCH linker of Qi and form the modified dianthin-EGF-SO1861 conjugate as suggested by the combined teachings of Bhargava and Qi.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a