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 .
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, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 40-47 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Note: for the purpose of the rejection PG Pub 2024/0043661 was utilized.
SPECIFICATION:
With respect to the cyclodextrin dimer instant specification states following:
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Which is read that the CD of the instant invention alone can be utilized in methods of claims 21, 37, 43 and 46 or that they can be combined with another medical component such as inhibitors [0060] or drugs (statins) [0062] to name a few.
[0387] is directed to disease indications and methods of treatment which is directed at solubilization and/or removal of 7KC which may be performed in vitro or in vivo, followed by discussion of the CD greater affinity and/or solubilization of 7KC than cholesterol which is evidenced at sub-saturating concentrations.
[0397] discloses the same language as instant claims 21, 37, 43 and 36 which is directed to a therapeutic method. The same list is disclosed in [0392].
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Examples provided by the applicants include following:
Example 1 [0429] MD simulations of βCDs and βCD dimers
Example 2 [0435] MD Simulation of C6 butyl-substituted DS6 triazole linked βCD Dimers complexes with sterols.
Example 3 [0437] MD Simulations of C6 2-hydroxypropyl DS6 triazole-linked βCD.
Example 4 [0443] is directed to solubilization of compounds by βCD.
Examples 5-9 [0444-0664] Synthesis of HPβCD substituted CD dimers. The examples include homodimers, asymmetric dimers and heterodimers.
Example 10 [0665] is directed to test methods, the sample was taken from healthy volunteers and plasma was spiked with 7KC. Results starting [0675] show that the affinity of the CD dimers is greater for 7KC than it is for cholesterol. Further tests included toxicity of dimers and their linking groups, solubility and study of the degree of substitution.
Case law holds that applicant's specification must be "commensurately enabling [regarding the scope of the claims]" Ex parte Kung, 17 USPQ2d 1545, 1547 (Bd. Pat. App. Inter. 1989) otherwise undue experimentation would be involved in determining how to practice and use applicant's invention. Although the statute itself does not use the phrase "undue experimentation", it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation as stated in Ex parte Forman, 230 USPQ 546, 547 (Bd. Pat. App. Inter. 1986) and in In re Wands, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Specifically, in In re Wands the Court set forth a non-exhaustive list of factors to be considered in determining whether undue experimentation would be involved in making and/or using the claimed invention. These factors include, but are not limited to : (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
It should be noted that while all Wands factors have to be considered, not all Wands factors need to be addressed in every case (MPEP 2164). The analysis is fact-dependent, and the decision to reject a claim based on scope of the claim relative to the scope of enablement must identify the claimed subject matter for which the specification is not enabling.
Instant claims 21, 37, 43 and 46 are directed to a therapeutic method comprising administration of effective amount of a cyclodextrin dimer (CD) dimer wherein the method can reduce the amount of 7KC and/or prevent, treat, ameliorate the symptoms of the diseases listed in the claims.
Claims 21, 37, 43 and 46 are rejected under 35 U.S.C. 112 first paragraph because the specification while enabling for specific dimers to trap 7KC toxin in host-guest type relationship, the specification does not enable one of ordinary skill in the art to which it pertains or with which it is most clearly connected to make and use the invention commensurate in scope of these claims.
Applying Wands factors to claims 21, 37, 43 and 46, it is noted that the specification provides no direction or working examples (cf. factors (f) and (g)) which would actually show how the claimed diseases are treated and there are no predictable results which would show that CD can treat all the listed diseases.
With respect to the diseases encompassed by claims 21, 37, 43 and 46 while CDs may reduce the content of the 7KC, such reduction in 7KC as shown in the examples does not constitute predictable result with respect to treating the diseases themselves which includes preventing the disease, threating the diseases or ameliorate the diseases. First issue that jumps out is the fact that the list includes diseases that are genetic. To fix the genetic disease one has to first fix genetic anomaly before attempting treatments utilizing inventive dimers.
Atherosclerosis/coronary artery disease is influenced by both genetic and environmental factors wherein approximately 40% are based on genetics due to mutations in the LDL receptor gene (PCSK9, SVEP1). These genes influence lipid metabolism, inflammation and vascular remodeling highlighting the complex polygenic nature of atherosclerosis.
Heart failure (all stages) is so generic in scope and is a complex condition that can result from multiple causes including genetic predisposition. These include cardiomyopathies such as dilated cardiomyopathy or hypertropic cardiomyopathy which are associated with specific gene mutations.
Alzheimers disease is influenced by combination of gene, life style and environmental factors, wherein early onset alzheimers is manifested in genes APP, PSEN1 and PSEN2.
Amyotropic Lateral Sclerosis Genetic (ALS) can also have genetic component to is specifically in noncoding hexanucleotide repeat of expansion in the C9 or F72 gene. Other genes include SOD1, TARDBP and FUS.
Huntington’s diseases is a genetic neurodegenerative disorder characterized by Chorea, which involves involuntary, dance-like movements along with cognitive and psychiatric symptoms. This is due to mutation in HTT gene.
Multiple sclerosis while not directly hereditary, there are over 200 genes that may influence susceptibility to this disease.
Smith-Lemli Optiz syndrome is caused by genetic mutations also known as pathogenic variants which occur randomly when cells are dividing. Specifically, mutation in the enzyme 7-Dehydrocholesterold reductase encoded by the DHCR7 gene.
Infantile neuronal ceroid lipofuscinosis is genetic. It is inherited as a recessive autosomal genetic trait.
Lysosomal acid lipase deficiency is caused by mutation in the LIPA gene which is essential for lipid metabolism in the body.
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive genetic disorder cause by mutation in the CYP27A1 gene, leading to cholesterol accumulation in various tissues.
Adrenoleukodystrophy is a genetic disorder caused by mutation in the ABCD1 gene located on the X chromosome, which means that the defective gene is on the X chromosome.
Sickle cell diseases is a genetic disorder caused by mutations in the HBB gene inherited from both parents when child inherits two copies of the abnormal hemoglobin S gene.
Niemann-Pick disease is inherited in an autosomal recessive pattern with certain types more common in specific population (Ashkenazi Jews for type A and B; French-Canadian or Nova Scotian population for type C). It is caused by mutation in specific genes SMPD1 (type A and B) and NPC1 or NPC2 gene (type C).
Gaucher disease is caused by mutations in the GBA gene which provides instructions for making the enzyme glucocerebrosidase that breaks down a fatty substance glucocerebroside.
Stargardt disease is caused by mutation of ABCA4 gene which is a biallelic mutation on chromosome 1.
Age-related macular degeneration (AMD) also has a genetic component and there are over 30 genes associated with AMD. The most notable ones include ARMS2/HTRA1 and Factor A and B genes.
Idiomathic pulmonary fibrosis (FPF) specifically familial FPF stems from pathogenic variants in genes such as TERT, TERC, PARN, DKC1 and NAF1, which is not by any means an exhaustive list.
Chronic Obstructive pulmonary disease (COPD) can be cause by SERPINA1 gene mutation and alpha-1 antitrypsin deficiency.
Cystic fibrosis disorder is caused by mutations in the CFRT gene and is inherited in autosomal recessive manner.
Non-alcohol steatohepatitic (NASH) is associated with mutations in PNPLA and TM6SF2 genes which are directly linked to the development and progression disease.
While non-alcoholic fatty liver disease is not caused by single inherited gene, genes play a significant role in determining susceptibility through PNPLA3 gene, ABHD5 gene and TM6SF2 gene.
Irritable bowel syndrome has a genetic component that is not cause by single gene mutation. It is results from a polygenic risk which is combined effect of many small genetic variations in contributing a small amount to overall susceptibility.
Crohn’s disease has over 200 genetic variations influencing susceptibility which stems from a combination of genetic environments and immune system factors, which key genes being NOD2, ATG16L1, IL23R and IRGM.
Hypercholesterolemia, specifically familial hypercholesterolemia is a genetic condition that leads to high level of low-density lipoprotein increasing risk of heart disease. Specifically, Mutation in LDLR gene, which encodes the low-density protein receptor.
Ulcerative colitis has a genetic component with family history and specific gene variation.
Consequently, there is no proof or any factual data in the applicant’s specification that their inventive CD dimer can prevent, treat or make these diseases better. Application fails to show that the genetic flaws can actually be fixed by cyclodextrin. There is a big difference between preventing the genetic disease, treating the genetic disease or making it better (ameliorating) and managing the genetic disease. There is nothing in applicant’s specification that would substantiate limitations of claims 21, 37, 43 and 46 because its CDR dimers have affinity for 7KC, which is one of many toxins or harmful substances present with these diseases. Evidence is required for each disease claimed.
Claims 1, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 40-47 are rejected under 35 U.S.C. 112 first paragraph because the specification while enabling for specific dimers to trap 7KC toxin in host-guest type relationship, the specification does not enable one of ordinary skill in the art to which it pertains or with which it is most clearly connected to make and use the invention commensurate in scope of these claims.
Applying Wands factors to claims 1, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 40-47, it is noted that the specification provides no direction or working examples (cf. factors (f) and (g)) which would show how different L and R substituents influence dimer’s ability to “trap” any possible toxin since instant claims are not limited to 7KC.
Human body has many substances that are formed within other than 7KC which are also reasons why listed diseases are progressing the way they.
The inventive CDs, for lack of better expression, form a pocket or an opening in which the guest molecule (in instant examples 7KC) has to fit. The lock and key concept only applies to components that can fit within that pocket or opening. However, not all toxins or harmful substances are created equal. 7KC is only one of the ketocholesterols produced by the body. Depending on the disease these substances include protein deposits, reactive oxygen species (ROS), sugars reacting with protein or lipids, uric acid produced by breakdown of hyperuricemia, prions, hormonic imbalance, cytokines, or prostaglandins just to name a few.
It should also be noted that 7KC is created by lipids, particularly cholesterol-containing lipoprotein and lipids are not created equal. Other substances produced that are harmful include 7-hydroxycholesterol, 27-hydroxycholesterol, cholestane-2one, lipid peroxidation products such as malondialdehyde, 4-hydroxynonenal and xox-acyl0hydroxyacids and so on.
Instant claims 1, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 40-47, under the broadest reasonable interpretation encompass all harmful substances, and yet none of the examples show if these toxins can even fit within the “pocket” of the inventive CD.
Additionally, based on the extensive content of the functional L and R groups in claims the inventive CD can be modified beyond what is taught by the instant invention, the specification does not show any factual evidence which would show how the inventive CDs can be modified with which group to effectively change the affinity to specific toxin or if each one of the substituents will provide the same affinity to the 7KC.
Furthermore, the definition of linking groups A, B and A’ is very extensive while the toxicity test is only performed on specific linking groups utilized in the examples. As such there is no showing or factual evidence that the other listed compounds (substituents and linking groups) would or would not be toxic for use within human body. The quantity of experimentation (cf. factor (h)) involved to reach usable embodiment from all the listed options would be too great. In view of the above discussion of the factors, it is concluded that undue experimentation would be involved to make and use of the invention as presently claimed with predictable results. The quantity of experimentation required to figure out which inventive dimer is actually the option for each of the diseases listed it enormous and will require extensive amount of time to figure out which one modification is best for each disease, which are very distinct from one another without even considering if they can be prevented, treated or made better. It should further be noted that it is not clear what the applicants consider as “better”.
Further instant specification does not show if all substituents or linking groups are safe for use in human body.
Instant specification further teaches that the inventive dimers can be utilized in combination with pharmaceutically acceptable therapy compounds. The specification is generic at best [0022] and [0023] that it includes any possible drug or treatment compound without significant toxicity, irritation or allergic response. CD dimers are not only known as compounds that can trap harmful toxins but also as a delivery vehicle for the drugs or therapeutically acceptable compounds. Instant specification again failed to show that if CD dimer is to be used as delivery vehicle for medicine that all those therapeutic compounds can fit within CD pocket to be delivered. This is because under broadest reasonable interpretation, instant invention includes using CD as delivery vehicle.
The examiner suggests cancellation of the claims directed to therapeutic method along with the diseases. All dependent claims inherit the deficiencies of independent claims.
Note: One of ordinary skill in the art has a bachelor’s or master’s degree and 5 years or less of work experience (NC State Science and Research – Polymer Chemist, 2021, p. 1-6). This allows one of ordinary skill to conduct routine experimentation under the guidance and direction of individuals with significantly higher levels of education and/or experience exceeding the level of ordinary skill in the art (D – level of one of ordinary skill). As discussed in MPEP 2164.03, chemistry is recognized as an unpredictable art (E – level of predictability in the art).
The rejection made is based on broad teachings of the instant claims. Amendment to the claims may require restriction and/or election of species may be required while the application is already in process of being examined.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 40-47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1, 7 13 and 24, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Specifically, the definition of R3’ is recited as halogen “SUCH AS” F, Cl, Br or I.
Claims 1, 7, 13, 24 are rendered as indefinite claims since it contains an improper Markush language. According to MPEP 2173.05(h) the Markush language may recite for example:
“...wherein R is selected from the group consisting of A, B, C and D”, or
“...wherein R is A, B, C or D”.
Claims 1, 7, 13 and 24 are confusing for following reasons:
Instant independent claims define groups L1 through L3’ indicating that at least one of these groups is a bond and corresponding R1-R3’ is N3, SH or a halogen.
Below this limitations R1-R3’ are defined including long list of compounds with various functional groups, such as alkoxy compounds, heteroalkyls, alkyls carbonyls and the like. Based on the requirement that one of the L groups has to be a bond, the respective R substituent cannot be selected from all the compounds disclosed, since the definition of R groups includes compounds outside of the scope of N3, SH or halogen. The limitation is confusing as it does not specifically state which L group is a bond and which R group is limited to comply with requirements of the independent claims.
Claim 13 requires presence of at least one linking group. Since each linking groups A, B and A’ can all be a bond, the remaining part of the claim does not make clear sense because L1 or L2 would become the linking group.
All dependent claims inherit the deficiencies of independent claims.
Claim Objections
Claims 1, 7, 13, 24 objected to because of the following informalities: CH2CH(OH)CH2N(CH3)3+ is improper. Appropriate correction is required.
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 40 and 41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aime et al. New cyclodextrin dimers and trimers capable of forming supramolecular adducts with shape specific ligands (Article attached).
With respect to claim 1, Aime discloses following structure:
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Wherein L1’ and L2’ are oxygen, R1’ and R2’ are hydrogen. The 7th group is modified to accept linking groups for dimerization wherein Ls is a bond and one of the Rs is N3. Wherein linking groups, A and A’ can be a bond and linking group B is substituted arylene.
With respect to claim 2, R1, R1’, R2, R2’ are hydrogen, depending which group will be utilized to bond to linking groups, R3 and R3’ can also be hydrogens.
With respect to claim 40, method of Aime is first to protect the hydroxy groups which process includes incorporating of functional group that allows formation of dimer via linking group. The resulting dimers are deprotected. Purification of the dimer is a requirement if its use is in medical delivery system which renders the purification as step that is not only inherent but necessary to avoid toxicity.
With respect to claim 41, Aime teaches use of spacers (linking groups) that are based on azido methyl compounds (p. 371) which form alkylated triazole bridges upon dimerization. On p. 370 Aime talks about forming both homodimers and heterodimers, wherein content of the substituents n and m are disclosed as well.
Claims 7, 8, 24, 42 and 43 are rejected under 35 U.S.C. 102(a)(1) or 102 (a)(2) as being anticipated by Aime et al. New cyclodextrin dimers and trimers capable of forming supramolecular adducts with shape specific ligands (Article attached).
With respect to claim 7, Aime discloses following structure:
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Wherein L1’ and L2’ are oxygen, R1’ and R2’ are hydrogen. The 7th group is modified to accept linking groups for dimerization wherein Ls is a bond and one of the Rs is N3. Wherein the linking groups A and A’ can be a bond and linking group B is substituted arylene. Aime discloses on page 370 that the CDs can be α-, β- and γ-CDs to make homodimers or heterodimers vis cycloaddition of CD monoazides and CD monoacetylenes.
With respect to claim 8, R1, R1’, R2, R2’ are hydrogen, depending which group will be utilized to bond to linking groups, R3 and R3’ can also be hydrogens.
With respect to claims 42 and 43, Aime clearly states in the introduction that the cyclodextrins are mixed with pharmaceutical agents as delivery agents, drug encapsulation and the like (P. 370). Wherein effects of the method are optional. Encapsulation of the drug by CD dimer is by definition solubilization of an otherwise hydrophobic drug.
With respect to claim 44, method of Aime is first to protect the hydroxy groups which process includes incorporating of functional group that allows formation of dimer via linking group. The resulting dimers are deprotected. Purification of the dimer is a requirement if its use is in medical delivery system which renders the purification as step that is not only inherent but necessary to avoid toxicity.
Aime teaches use of spacers (linking groups) that are based on azido methyl compounds (p. 371) which form alkylated triazole bridges upon dimerization. On p. 370 Aime talks about forming both homodimers and heterodimers, wherein content of the substituents n and m are disclosed as well.
Claims 13, 14 and 45-47 are rejected under 35 U.S.C. 102(a)(1) or 102 (a)(2) as being anticipated by Aime et al. New cyclodextrin dimers and trimers capable of forming supramolecular adducts with shape specific ligands (Article attached).
With respect to claim 13, Aime discloses following structure:
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Wherein L1’ and L2’ are oxygen, R1’ and R2’ are hydrogen. The 7th group is modified to accept linking groups for dimerization wherein Ls is a bond and one of the Rs is N3. Wherein linking groups, A and A’ can be a bond and linking group B is substituted arylene.
With respect to the provisos at least one L/R group will be different from the rest because it will be bound to the linking groups. Since the applicants have not defined which group is beings substituted, at least one proviso is met. Furthermore, under broadest reasonable interpretation only one L or R has to be different in order to make the entire pair different.
With respect to claim 14, R1, R1’, R2, R2’ are hydrogen, depending which group will be utilized to bond to linking groups, R3 and R3’ can also be hydrogens.
With respect to claim 45, Aime clearly states in the introduction that the cyclodextrins are mixed with pharmaceutical agents as delivery agents, drug encapsulation and the like (P. 370). Wherein effects of the method are optional. Encapsulation of the drug by CD dimer is by definition solubilization of an otherwise hydrophobic drug.
With respect to claim 46, Aime clearly states in the introduction that the cyclodextrins are mixed with pharmaceutical agents as delivery agents, drug encapsulation and the like (P. 370). Wherein effects of the method are optional. Encapsulation of the drug by CD dimer is by definition solubilization of an otherwise hydrophobic drug.
With respect to claim 47, method of Aime is first to protect the hydroxy groups which process includes incorporating of functional group that allows formation of dimer via linking group. The resulting dimers are deprotected. Purification of the dimer is a requirement if its use is in medical delivery system which renders the purification as step that is not only inherent but necessary to avoid toxicity.
Aime teaches use of spacers (linking groups) that are based on azido methyl compounds (p. 371) which form alkylated triazole bridges upon dimerization. On p. 370 Aime talks about forming both homodimers and heterodimers, wherein content of the substituents n and m are disclosed as well.
Claims 24, 25, 36 and 37 are rejected under 35 U.S.C. 102(a)(1) or 102 (a)(2) as being anticipated by Aime et al. New cyclodextrin dimers and trimers capable of forming supramolecular adducts with shape specific ligands (Article attached).
With respect to claim 24, Aime discloses following structure:
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Wherein L1’ and L2’ are oxygen, R1’ and R2’ are hydrogen. The 7th group is modified to accept linking groups for dimerization wherein Ls is a bond and one of the Rs is N3. Wherein linking groups, A and A’ can be a bond and linking group B is substituted arylene.
With respect to claim 25, R1, R1’, R2, R2’ are hydrogen, depending which group will be utilized to bond to linking groups, R3 and R3’ can also be hydrogens.
With respect to claims 36 and 37, Aime clearly states in the introduction that the cyclodextrins are mixed with pharmaceutical agents as delivery agents, drug encapsulation and the like (P. 370). Wherein effects of the method are optional. Encapsulation of the drug by CD dimer is by definition solubilization of an otherwise hydrophobic drug.
Claims 1, 2 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by De Jong article.
With respect to claims 13 the DeJong discloses the complexation of β-cyclodextrin (CD) with guest molecules and use of the of the CD as sensor molecules by covalently attaching the fluorophore such that the generation of signal is based on the competition for cyclodextrin cavity between the covalently attached fluorophore and an added guest (p. 4034 para 2) which complexes strongly with steroidal bile salts (Abstract). The CD are connected through their secondary sites (p. 4035, Para 2) at the C2 position (P. 4035 para 5). This structure is a CD dimer of the instant invention in which L1-3 and L1’-L3’ are oxygen, R1-3 and R1’-3’ are hydrogen. Linking groups include substituted heteroalkene.
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Claim 13 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by De Jong article.
With respect to claims 13, the DeJong discloses the complexation of β-cyclodextrin (CD) with guest molecules and use of the of the CD as sensor molecules by covalently attaching the fluorophore such that the generation of signal is based on the competition for cyclodextrin cavity between the covalently attached fluorophore and an added guest (p. 4034 para 2) which complexes strongly with steroidal bile salts (Abstract). The CD are connected through their secondary sites (p. 4035, Para 2) at the C2 position (P. 4035 para 5). This structure is a CD dimer of the instant invention in which L1-3 and L1’-L3’ are oxygen, R1-3 and R1’-3’ are hydrogen. Linking groups include substituted heteroalkene.
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Claim 24 and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by De Jong article.
With respect to claims 24 and 25, the DeJong discloses the complexation of β-cyclodextrin (CD) with guest molecules and use of the of the CD as sensor molecules by covalently attaching the fluorophore such that the generation of signal is based on the competition for cyclodextrin cavity between the covalently attached fluorophore and an added guest (p. 4034 para 2) which complexes strongly with steroidal bile salts (Abstract). The CD are connected through their secondary sites (p. 4035, Para 2) at the C2 position (P. 4035 para 5). This structure is a CD dimer of the instant invention in which L1-3 and L1’-L3’ are oxygen, R1-3 and R1’-3’ are hydrogen. Linking groups include substituted heteroalkene.
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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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 8, 14, 20, 21, 24, 25, 36, 37, are rejected under 35 U.S.C. 103 as being unpatentable over Aime in view of Schwarz (J. International Pharma article).
Discussion of the teachings of Aime are incorporated here by reference. While Aime teaches dimers and while encapsulation is viewed as solubilizing, Aime does not show how tailor the selectivity of the CD dimers via adjusting functional groups and linking groups.
Schwarz discloses solubilizing steroidal drugs using β-CD derivatives. Specifically, that CD derivatives can solubilize steroids and improve bio-availability of these hydrophobic APIs (Abstract).
CDs are host molecules because they are able to complex with guest molecules in aqueous media. It is known that complexes with two CDs rings per guest can be formed. Substitution of the primary hydroxy group of CD by the more hydrophobic thioether groups improves the binding potential so that exceptional high binding constants can be reached.
Schwarz states that binding depends on the special fit of the guest within the CD cavity and on the pattern of substituents on the CD derivative. The more completely the hydrophobic guest is filling the cavity, the higher will be the binding constant (pp. 560-561). Schwarz states that there is a high demand in finding improved formulation for steroidal drugs using cyclodextrin derivatives which provide several advantages including avoiding harmful excipients such as ethanol, DMSO and surfactants, enhanced rate of uptake, higher dosage efficiency and reproducibility and more convenient administration forms such sublingual administration (p. 564, papa 4).
The derivatives discussed by Schwarz include heptakis-6-thioglyceryl-6-deoxy-β-CD (HTG)(Abstract).
HTG is a cyclodextrin derivative of the instant claims wherein instant L1, L1’, L2, L2’ are each O, L3 and L3’ are S. R3 and R3’ are hydroxyalkyl (Scheme 1. HTG showed selective recognition of β-estradiol by exclusively complexing the female hormone over testosterone (p. 564, para 2).
Schwarz teaches that the β-CD HTG derivative can solubilize steroids to increase serum level, which can be avoided by attaching CD to a polymer backbone.
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The formula meets the structure of instant claims 1, 2, 13, 14, 24, 25.
With respect to the reduction of 7KC such as included in claims as optional effect. Additionally, since the CDR Dimers of prior art comprises the same functional groups and linkers, the affinity to 7KC is viewed as inherent.
In the light of the above disclosure, it would have been obvious to one having ordinary skill in the art that CD dimers would solubilize the hydrophobic drugs and that the affinity of the CD dimer can be adjusted depending on the target compound. Such modification would allow one of ordinary skill in the art to provide a dimer having optimized efficiency for specific target compounds for either delivery or removal.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 42, 43, 46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 11,279,774 to O’Connor. Although the claims at issue are not identical, they are not patentably distinct from each other because:
O’Connor teaches cyclodextrin dimer having CD-L-CD structure in patented claim 1, wherein L is a linker and CD has following structure:
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Wherein instantly claimed L group is an oxygen, and R is defined in the same manner as that of the instant invention. The linking group of O’Connor is much broader in scope as the linking group B of the instant invention wherein A and A’ are bond. Specifically, the linking group is 6-8 atoms comprising any functionality or chemical structure. Instant group B can also be heteroarylene which meets the formula of claim 4 of O’Connor.
O’Connor in claim 2 further discloses narrow embodiments of the substituents that fall within the scope of instant independent claims 1, 7, 13 and 46 as well as dependent claim 14.
The dimer of O’Connor can be utilized with pharmaceutically acceptable carrier. Consequently, instant invention is viewed as broader disclosure of already patented invention of O’Connor.
Claim 1, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 40-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,157,779 (‘779). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Patented invention (also to Connor) discloses a dimer having CD-L-CD structure, wherein CD is defined in claim 1 as follows:
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Wherein L in the patented ‘779 is a linking group having no more than 22 atoms which meets the definition of instant linking group B, where linking groups A and A’ are bonds. Patented linking groups are specifically substituted heteroaryls.
Oxygen atom meets instant groups L1, L2, L3, L1’, L2’ and L3’. Groups R1, R2 and R3 of ‘779 are defined in the same manner as groups R1, R2, R3, R1’, R2’ and R3’ if the instant invention.
Dimers of ‘779 also are taught to prevent, treat and ameliorate the same type of diseases either alone or in combination with another type of therapy/drug.
The method of ‘779 is the same method of making the dimer as that disclosed in the instant invention.
Claim 1, 2, 7, 8, 13, 14, 20, 21, 24, 25, 36, 37, 40-47 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-12, 25, 37, 42, 44, 54, 62, 63, 72 of copending Application No. 18/925129 )’129). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Co-pending application ‘129 discloses CD dimers having CD-L-CD structure and wherein CD has several formulae that meet instant invention the substituents meet the instantly claimed compound. The linking group is heteroaryl compound, instant group L is Oxygen and all R substituents are defined in the same manner.
The method of making the dimers is also the same as method of making dimer of the instant invention including materials utilized therein.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1, 2, 13, 14, 20, 21, 40, 41, 45-47 rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1, 2, 13, 14, 20, 21, 40, 41, 45-51 of prior 17/369,791 (‘791)This is a statutory double patenting rejection.
Please note that this application was allowed on 2/27/2026. Latest claimed of the applications are utilized in the rejection because patent has not been published and the number has not been assigned yet.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims are almost identical and very much coextensive in scope. That is the claims in both applications cover subject matter.
Relevant Prior Art
IDS submitted with this office action discloses several articles that are viewed as pertinent to the prior art of record. These include articles of Cravotto, Lau, Moser, De Jong and Breslow.
Conclusion
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/KATARZYNA I KOLB/Primary Examiner, Art Unit 1767 May 26, 2026
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