DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application is the U.S. National Stage Application, pursuant to 35 U.S.C.371, of PCT International Application No. PCT/US2021/063848 filed December 16, 2021 which claims priority to US Provisional Application No. 63/126,389 filed December 16, 2020.
Status of the Claims
Applicant has filed arguments on February 3rd, 2026 in response to the Office Action dated November 5th, 2025; no amendments or new claims have been added. Claims 1-11, 16-23 and 30 are pending and are examined on their merits.
35 U.S.C. § 103 Rejections Maintained
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 1-3, 6-11, 16-22 and 30 are unpatentable over US 10,272,055 B2 in view of Reekie
Claims 1-11, 16-23 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,272,055 B2, Potter et.al., April 30, 2019 hereinafter ‘055, in view of Reekie, et. al, Cubanes in Medicinal Chemistry, J. Med. Chem. 2019, 62, 1078−1095.
Response to Applicants Arguments under 35 US§ 103 Rejections
Applicant purports the claimed compounds exhibit unexpected advantages that cannot be reasonably expected in view of the '055 Patent and Reekie. The present disclosure relates to hexyl-cubanyl-biguanide (HCB) and its derivatives, which contain a cubanyl-substituted
alkyl chain at the R1 position and that there are examples of the present disclosure providing substantial evidence to demonstrate that the cubanyl compounds show unexpected improvements in potency and pharmacological properties over the phenyl-substituted HBB. The applicant provides examples A and B from the specification.
Example A - teaches that "[c]ubanes have the same size of the phenyl moiety,
but are aliphatic rather than aromatic, and may thereby exhibit higher affinity binding to the
CYP3A4 target, lower electrophysiological risk of heart arrhythmias, and decreased CYP mediated metabolism through phenyl ring hydroxylation. Applicant further points to docking studies in the specification that cubane derivatives are expected to be more potent inhibitors of CYP3A4 AA epoxygenase activity, with decreased electrophysiological risk and higher likelihood of crossing the blood brain barrier compared to HBB.
The arguments of the applicant that [c]ubanes have the same size of the phenyl moiety,
but are aliphatic rather than aromatic is not in dispute. The applicant only points to docking studies, which are computational techniques to predict the interactions between small molecules and target proteins. The genus of the instant compound of claim 1 and the compounds as taught by US 10,272,055 B2, Potter et.al., April 30, 2019 hereinafter ‘055 are both inhibitors CYP3A4 epoxygenase and are both evaluated for treating or preventing breast cancer (e.g., estrogen positive breast cancer (ER+ breast cancer), estrogen positive HER2 negative breast cancer (ER+ HER2-). The compounds of HBB and the HCB are compared to each other in addition to fluorinated variations of the HCB compound (HCB-F2, HCB-F3 and HCB F5) The table 1 from the Applicant’s specification shows the Dock scores of the various compounds, as shown below.
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The Surflex-Dock score does not seem to show significantly different scores from HBB and among the HCB compound and its variations identified in the figure. The argument for example A is not convincing.
Example B- applicant suggests HCB's unexpected selectivity for CYP3A4 and
inhibition of biosynthesis of ( ±) 14, 15-EET regioisomer may contribute to the more potent activity against ER-positive/HER2-negative breast cancer, compared to HBB. Further, the applicant’s purport their compounds increased off-target effects on the cardiovascular system including hypertension and smooth muscle injury because the HBB biguanides do inhibit CYP2J2 which is cardioprotective and point to Tables 1 and 2 for evidence. Table 1 is shown above, Table 2 is shown below that indicates electrophysiological risk.
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In this case, HCB-F2 (a difluorinated variant of HCB) shows a greater protective aspect to electrophysiological risk than HCB. The applicant continues to point at the differences between HCB and HBB but omits any discussion of the variants of HCB that show nearly identical responses to HBB in both docking scores and electrophysiological risk. The arguments for Example B are not convincing.
Applicant argues in Example C, that the antiviral activity of HBB and HCB using two assays performed on African green monkey kidney cells and human embryonic kidney cells. In both assays, HCB showed higher potency than HBB as antivirals. Specification, Figures 11 and 12. According to the applicant’s specification on page 38 To test whether HBB or HCB exhibits antiviral activity, two assays were used and compared to Remdesivir (a known Covid 19 antiviral; used as a control). In the first assay, show in in Figure 11, in Vero cells (African green monkey kidney cells), remdesivir was compared with HCB and HBB. Figure 11 is shown below.
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The comparison of cytotoxicity activity among Remdesivir, HBB and HCB show that HBB has a lower CC10 (.091 µM) than both HCB (0.201 µM) and Remdesivir (1.037 µM) and identical CC50 (>20 µM) value compared to the control in the experiment; Remdesivir. Further, the antiviral comparison of the IC90 values of HBB (>20 µM) and HCB (19.664 µM) do not appear to be significantly different.
Figure 12 shows a second assay performed in 293T human embryonic kidney cells over-expressing the ACE2 receptor for SARS-CoV-2. In the 293T/ACE2 assay remdesivir was compared with HCB and HBB. Remdesivir showed an antiviral IC50 of 0.02 μM an IC90 of 0.022 μM. In the cytotoxicity assay, the CCl0 and CC50 values were both> 0.1 μM. HCB showed an antiviral IC50 of 0.7 μM and an IC90 of 4.8 μM. The CC 10 was 1. 04 μM and the CC50 7.2 μM. The experiment testing HBB showed an antiviral IC50 of 0.82 μM and an IC90 of 11.3 μM. In the cytotoxicity assay, the CCl0 was 1.5 μM and the CC50 26μM (Page 38 of the specification). The applicant’s argument suggesting that HCB is significantly more effective than HBB in this case is not compelling with respect to the IC50 values. The IC50 values of HCB (0.7 μM) and HBB (0.82 μM) are not significantly different especially when compared to the IC50 of the control group; Remdesivir (0.022 μM).
Contrary to the applicant’s remarks the applicant would have a reasonable expectation of success utilizing the core compound of ‘055 replacing the phenyl group with a cubanyl as taught by Reekie. Specifically, Reekie teaches a histone deacetylase inhibitor of an approved treatment for T-cell lymphoma where the phenyl group is replaced by a cubanyl group and shows that the side-by side comparison of the two obtained comparative IC50 values against tumor cells, but notes that the cubanyl substitution was less toxic to the primary cells. Applicant points to Reekie’s evidence showing the treatments did not show any significant difference in the IC50 values identified by Reekie as log PHPLC values of 0.99 (phenyl) vs 1.52 (cubanyl); 152% improvement with the cubanyl substituted for the phenyl group. The only examples that the applicant points to with IC50 data is Figure 11 and 12 where the difference in percent is comparing HCB and HBB is 128% (Figure 11) and 117% (figure 12); both examples relating the antiviral advantages of HCB. Reekie teaches two distinct advantages in the treatment of T-cell lymphoma by substituting a cubanyl for a phenyl, showing a 152% increase in effectiveness of the cubanyl over the phenyl, therefore the applicant’s arguments regarding the teaching of ‘055 and Reekie are not convincing.
Applicant argues that Brown does not address the claims 4 and 5 because although he does teach the isosteric replacement of halogens with hydrogens, the combination of the '055 Patent and Reekie does not teach or suggest the claimed invention. Brown fails to cure this deficiency. Brown relates to bioisosterism in medicinal chemistry and does not teach or suggest the unexpected benefits of cubanyl compounds over their phenyl counterparts, as demonstrated by the claimed compounds.
Applicant continues to argue that claim 1 is not obvious over ‘055 (which identifies the core compound) and Reekie (that teaches the substitution of a cubanyl for a phenyl) and Brown who teaches the further limitation of the isosteric replacement of halogens for hydrogens does not arrive at the claimed invention of claim 4 (that identifies a halo-substituted alkyl) and the specific compounds of claim 5. These arguments are not convincing.
Applicant argues that claim 23 is not taught by Krebs and relates to polyhexamethylene biguanide compounds and their activity against HIV type I. Krebs does not teach or suggest the unexpected benefits of cubanyl compounds over their phenyl counterparts, as demonstrated by the claimed compounds. Claim 23 is an independent claim that describes a method for treating a subject in need of a treatment for a viral infection, the method comprising administering an effective amount of a biguanide compound to the subject. Krebs teaches the use of a biguanide compound to treat type 1 HIV (a virus). Therefore, the applicant’s argument is not convincing.
35 USC § 103 Rejection Reiterated
By way of background, Applicant’s invention is directed to a compound that is a biguanide derivative of the diabetes drug metformin, that is currently being studied in breast cancer clinical trials. Other compounds such as, metformin and biguanides, buformin and phenformin, have been tested against cancer, and although exhibit inhibitory activity against breast cancer they lack potency and their mechanisms of action are unclear.
Claim 1 is directed towards a compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein R1 comprises a cubanyl-substituted
alkyl and R2 comprises a substituted or unsubstituted alkyl.
Similar to the Applicant’s claimed invention, ‘055 teaches in the Summary of the Invention (col. 1) compounds disclosed herein (e.g., compounds of formula I) have as one activity the ability to inhibit CYP3A4 epoxygenase. The use of the compound is composed of the same genus of a biguanides as the instant claim and in one embodiment provides a method for treating or preventing breast cancer (e.g., estrogen positive breast cancer (ER+ breast cancer), estrogen positive HER2 negative breast cancer (ER+ HER2-)) in a patient (e.g., mammal such as a human) and further, that compounds disclosed herein ( e.g., compounds of formula I) enhance the effect of other chemotherapeutic agents (e.g., chemotherapeutic agents for treating breast cancer) comprising administering to the patient in need thereof an effective amount of a compound of formula Ia and Ib. Formula Ib (col. 13) is detailed below:
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Wherein,
R1 is H, (C1-C12) alkyl, (C2 -C12) alkenyl, (C2 -C12) alkynyl,
30 ---O (C1 -C12) alkyl, -O (C2 -C12) alkenyl, ---O(C2-C12) alkynyl,
-OH, (C3 -C8) carbocycle, 5-10 membered heteroaryl
or aryl, wherein any (C1 -C12) alkyl, (C2-C12) alkenyl, (C2 -
C12) alkynyl, ---O
“A specific value for z 4a is a 5 membered heteroaryl, 6 membered heteroaryl or phenyl, wherein any 5 membered heteroaryl, 6 membered heteroaryl or phenyl of z 4a is optionally substituted with one or more groups selected from (C1 -C6) alkyl, -OH, halogen and ---O (C1 -C6) alkyl. A specific value for z 4a is a 5 membered heteroaryl, 6 membered heteroaryl or phenyl.”
‘055 also identifies (col. 13) one of the specific compounds as an example of the genus of formula I with the variables underlined above as:
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Although ‘055 teaches the same genus and a species that includes a phenyl group for z 4a variable and a, (C1-C12) alkyl for the R1 variable for formula Ib, that are useful for treating breast cancer, they do not teach the cubanyl-substituted alkyl identified as R1 of the instant claim. However, one of ordinary skill in the art would have reasonably expected by using the scaffold of the compound of formula I/Ib and the variables identified as z 4a and R1 as taught by ‘055 because the use of compounds of the genus and the species detailed above have been used to treat breast cancer.
Reekie teaches that there is a structure activity relationship between cubane moieties and phenyl groups (e.g. the two functional groups are isosteres). They also generate cubane analogs for known pharmaceuticals. For example,
“Structure−activity relationships (SARs) that incorporate the cubane moiety have normally involved it as an isostere for a phenyl group or as a substitute for cyclic or polycyclic functionality. Validation of Eaton’s hypothesis stating cubane is a benzene isostere has only recently been reported.40 In doing so, the authors investigated known pharmaceuticals and agrochemicals that contain phenyl rings and generated their cubane analogs.”
Reekie, pg.1080, col 2 (emphasis added).
“Two of the monosubstituted cubane derivatives are shown in Figure 4. Compound 36a (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor approved for treatment of cutaneous T-cell lymphoma.41,42 The cubane analog 36b, in a side-by-side assessment with 36a, obtained comparative IC50 values against tumor cells and was significantly less toxic against neonatal foreskin fibroblasts (NFF) primary cells.40 Further comparisons were conducted in vivo, with both compounds demonstrating significant reduction in tumor growth compared to vehicle. Furthermore, both compounds performed almost identically in these studies. Experimentally determined log PHPLC values for 36a and 36b were also reported as 0.99 and 1.52, showing an increase of lipophilicity by substituting a phenyl for cubanyl moiety.”
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Figure 4. Examining cubane as a substitute for a phenyl group.
Reekie, pg.1080, col 2 pg. 1081, col 1. (emphasis added).
Accordingly, it would be prima facie obvious to one of ordinary skill in the art to substitute a cubane in place of a phenyl group that is taught by ‘055 because Reekie teaches that both functional groups are isosteres. A cubane substitution used in place of a phenyl of the same genus of the compound of formula I/Ib identified by ‘055, and the genus of formula I of the instant claim are identical.
Claim 2 further limits claim 1 wherein the compound is:
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As identified in the rejection to claim 1 above ‘055 also identifies (col. 13) one of the specific compounds as an example of the genus of formula I/Ib with the variables that include the phenyl group and a (C1-C12) alkyl as shown below.
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Therefore, claim 2 is obvious for the same reasons as claim 1 above.
Claim 3 further limits claim 1 wherein, the compound is:
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‘055 identifies method of screening molecules to identify a species as potential ER+ HER2- breast cancer therapeutics (e.g., Biguanides). Among the compounds tested that depend from formula I/Ib are two specific molecules that contain halogenated phenyl rings on either side of the compound of claim 1 above (col. 25 and 26). For example:
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and
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The substitution of 2 cubane molecules in place of two halogenated phenyl groups that is taught by Reekie are isosteres would be an obvious selection of a compound moiety of the formula I of claim 1. Accordingly, the instant claim is rejected for the same obvious reasons as claim 1 above.
Claims 6-8, 17 and 30 are drawn to the pharmaceutically acceptable salt of claim 1 being mesylate (claim 6), a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable excipient, diluent, or carrier (claim 7) and the pharmaceutical composition is formulated for subcutaneous administration (claim 8, 17 and 30).
‘055 in col. 17 details all of the variables listed in the instant claims including the pharmaceutical acceptable salts, the excipients and a subcutaneous administration. For example:
“Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate,and a-glyc- 10 erophosphate.”
“The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.”
Thus, the present compounds may be systemically admin- istered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, and the like.
The only clarification that needs to be made is that methanesulfonate and, mesylate are two terms for the same chemical group, an ester or salt of methanesulfonic acid (
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CH3SO3H)
mesylate is the common shorthand, while "methanesulfonate" is the full, more formal name. ‘055 teaches all of the limitations of the instant claims.
Accordingly, one of ordinary skill in the art would expect have success using the delivery motifs as identified by ‘055 for the same genus of compounds. Therefore, the invention of claims 6-8, 17 and 30 would be prima facie obvious at the time it was filed.
Claims 9-11 are drawn to method for treating a subject in need of a treatment for a cancer, comprising administering an effective amount of the compound according to claim 1 to the subject (claim 9), the subject is in need of a treatment for a breast cancer according to claim 9, (claim 10), the subject is in need of a treatment for an ER+ breast cancer, a HER2+ breast cancer, an ER+ and HER2+ breast cancer, an ER+ and HER2- breast cancer, or a HER2+ and ER- breast cancer according to claim 10, (claim 11) and the method of claims 9.to
As mentioned in the rejection to claim 1, ‘055 teaches the use of formula I/Ib the same genus of a biguanides and in one embodiment provides a method for treating or preventing breast cancer (e.g., estrogen positive breast cancer (ER+ breast cancer), estrogen positive HER2 negative breast cancer (ER+ HER2-)) in a patient (e.g., mammal such as a human) and further, that compounds disclosed herein (e.g., compounds of formula I).
Accordingly, one of ordinary skill in the art would expect that the biguanide compound of claim 1 would be effective at treating breast cancer ER+ breast cancer, a HER2+ breast cancer, an ER+ and HER2+ breast cancer, an ER+ and HER2- breast cancer, or a HER2+ and ER- breast cancer because ‘055 teaches the use of the same biguanide compound is useful for treatment of the same breast cancers.
Claim 16 further limits claim 10 wherein the subject is in need of a treatment for a
triple negative breast cancer.
Triple negative breast cancer (TBNC) is an aggressive type of breast cancer that tests negative for three receptors: Estrogen receptor (ER), Progesterone receptor (PR), and Human epidermal growth factor receptor 2 (HER2). Because TNBC lacks the receptors found in other breast cancers, treatment options like hormone therapy or HER2-targeted drugs are not effective and so the tumors tend to respond better to chemotherapy.
Although ‘055 is silent on triple negative breast cancer treatment, they do teach that:
“Applicant has also discovered that compounds disclosed wherein (e.g., compounds of formula I) enhance the effect of other chemotherapeutic agents (e.g., chemotherapeutic agents for treating breast cancer).”
‘055, col 1, Summary of the Invention, (emphasis added).
Therefore, it would be obvious to one of ordinary skill in the art to use the compound of Formula I as taught by ‘055 to treat a triple negative form of breast cancer with a reasonable expectation of success because ‘055 teaches that the genus of the compound of Formula I enhances the effect of chemotherapeutics that are used to treat triple negative breast cancer that are non-responsive to Estrogen receptor (ER), Progesterone receptor (PR), and Human epidermal growth factor receptor 2 (HER2) .
Claim 18 further limits claim 9 wherein the compound is co-administered with and immunotherapy.
Immunotherapy is a type of cancer treatment that uses the patient's own immune system to fight cancer cells. Two specific drugs identified as chemotherapeutic agents by ‘055 are, in fact, considered immunotherapies; namely trastuzumab and pertuzumab. Both drugs are considered immunotherapies because they use a monoclonal antibody that targets a protein called HER2, which is overexpressed in some types of breast cancer. By binding to HER2, trastuzumab and pertuzumab block the signaling pathway and weaken the cancer cells. For example:
“In one embodiment the chemotherapeutic agents are independently selected from tamoxifen, fulvestrant, raloxifene, anastrozole, letrozole, exemestane, paclitaxel, docetaxel, ixabepilone, eribulin, capecitabine, gemcitabine, vinorelbine, palbociclib, everolimus, trastuzumab, pertuzumab and lapatinib.”
‘055, col 16, paragraph 5 (emphasis added).
Therefore, one of ordinary skill in the art would use have a reasonable expectation of success using the compound of ‘055 in concert with an the immunotherapeutic such as trastuzumab or pertuzumab, because ‘055 teaches the use of both.
Claims 19-22 further limit claim 9 wherein the cancer is a CYP-dependent tumor or a mTOR-dependent tumor (claim19), the cancer is dependent on an EET for angiogenesis or nuclear signaling (claim 20) and the cancer is dependent on oxidative phosphorylation (claim 21) and wherein the cancer is a therapy-resistant cancer (claim 22).
As described in the rejection to claim 1 above, in the Summary of the Invention (col. 1) compounds disclosed herein (e.g., compounds of formula I) have as one activity the ability to inhibit CYP3A4 epoxygenase. ‘055 teaches that the inhibition of CYP3A4 and the synthesis of EETs (epoxyeicosatrienoic acids) are targets to treat cancer and specifically, breast cancer.
“The compounds of formula I (e.g., Ia, lb) (or salts thereof) described herein are useful for preventing or treating cancer including breast cancer and in particular estrogen positive breast cancer. One property of these compounds is their ability to inhibit CYP3A4 epoxygenase (such as inhibiting CYP3A4 epoxygenase activity which thereby inhibits the synthesis of epoxyeicosatrienoic acids (EETs).”
‘055, col 16, paragraph 2 (emphasis added), and,
“Compounds described herein (e.g., compounds of formula I or pharmaceutically acceptable salts thereof) may also increase the effectiveness of hormonal therapy in the metastatic setting using mTOR inhibitors such as everolimus and cyclin dependent kinase inhibitors such as palbociclib. Everolimus and palbociclib increase the effectiveness of hormonal therapy for recurrent metastatic disease but they don't increase the effectiveness of chemotherapy in ER+HER2- breast cancer. The major unmet need is to find a method to make chemotherapy more effective in ER+HER2- breast cancer.”
‘055, col 27, 28, paragraph 2 (emphasis added).
The teaching of ‘055 further detail in claim 2 of the invention, that using the biguanide compound Nl-hexyl-N5-benzyl biguanide (HBB) is inhibits the oxidative phosphorylation and thereby glycolysis in breast cancer cells. For example:
“2) detecting whether Nl-hexyl-N5-benzyl biguanide (HBB):
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or a pharmaceutically acceptable salt thereof, inhibits oxidative phosphorylation and glycolysis in the breast cancer cells by contacting the sample with HBB, or a pharmaceutically acceptable salt thereof, and measuring the oxygen consumption rate (OCR) and the extracellular acidification 50 rate (ECAR) in the breast cancer cells;”
‘055, col. 32, claim 2, (emphasis added).
Accordingly, one of ordinary skill in the art would expect to have success in treating breast cancer by using the compound of Formula I, that is detailed in claim 2 of ‘055. The compound is known to treat breast cancer because it is a known inhibitor of CYP3A4 epoxygenase activity and thereby the synthesis of epoxyeicosatrienoic acids (EETs), that also inhibits oxidative phosphorylation and glycolysis in breast cancer cells. The use of the compound to treat breast cancer that is susceptible to treatment by inhibiting the same metabolic pathways as ‘055 would be prima facie obvious at the time the application was filed.
Claims 4 and 5 are unpatentable over US 10,272,055 B2, Reekie et.al. and in further view of Brown, et.al.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,272,055 B2, Potter et.al., April 30, 2019 hereinafter ‘055, Reekie, et. al, Cubanes in Medicinal Chemistry, J. Med. Chem. 2019, 62, 1078−1095, and in further view of Brown, Bioisosteres in Medicinal Chemistry, 2012.
Claims 4 and 5 are directed to the compound of claim 1, wherein the R2 is a halo-substituted alkyl (claim 4) and the compounds that depend from claim 4 (claim 5), as shown below.
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The species of the compound identified in the rejection to claim 2 above has an alkyl group that has an unsubstituted methyl group (e.g. the binding sites of the alkyl chain are carbon atoms bonded to H atoms). The claimed compounds of the instant claims have a series of fluoro-substituted alkyls in place of the methyl groups of the compound of claim 2.
Brown teaches that isosteric replacements of halogens for hydrogens are known as a common approach to improve the metabolic activity of compounds. For example,
“One of the most common monovalent isosteric replacements is the substitution of hydrogen with fluorine [7]. These atoms have similar van derWaals radii but different electronic effects, fluorine being the most electronegative element in the periodic table. Due to the high strength of the C_F bond, fluorine is often introduced to achieve metabolic stability. Moreover, due to its high electronegativity, fluorine can be introduced to reduce basicity of proximal amines or increase acidity of proximal acids and also to introduce a conformational bias in molecules.”
Brown, pg. 17 (emphasis added).
Therefore, one of ordinary skill in the art would have reasonably expected that by substituting methyl groups in the alkyl chain of the compound of claim 2 with fluorine groups as taught by Brown because hydrogen and fluorine atoms are considered isosteric replacements.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over US 10,272,055 B2, Potter et.al., April 30, 2019 hereinafter ‘055, Reekie, et. al, Cubanes in Medicinal Chemistry, J. Med. Chem. 2019, 62, 1078−1095, and in further view of Krebs, Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1, Biomedicine & Pharmacotherapy, 59 (2005) 438–445.
Claim 23 is directed to method for treating a subject in need of a treatment for a viral infection, the method comprising administering an effective amount of a biguanide compound to the subject.
Krebs teaches the use of biguanide compounds, specifically polyhexamethylene biguanide (PHMB) which is a polybiguanide (PBG) oligomer to treat HIV type I. For example,
“The reported mechanism of PHMB antimicrobial activity, which involves interactions with cell membrane components,
suggested that PHMB or other PBG-based compounds might also have antiviral or virucidal activity against the human immunodeficiency virus type 1 (HIV-1). PHMB had modest in vitro activity against both cell-free and cell-associated HIV-1, as well as the ability to interfere with viral binding and entry.”
Krebs, pg. 438, Abstract (emphasis added).
Accordingly, one of ordinary skill in the art would have a reasonably expected that using a biguanide compound to treat a viral infection, like HIV type I, as taught by Krebs would be successful to treat the generic virus of the instant claim.
Double Patenting Rejection Maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-11,16-23 and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of Potter, et. al., U.S. Patent No.10,272,055 B2 issued on April 30, 2019 (hereinafter ‘505) and in view of Reekie, et. al, Cubanes in Medicinal Chemistry, J. Med. Chem. 2019, 62, 1078−1095.
Response to Applicants Arguments under nonstatutory double patenting rejection
For similar reasons as explained above, the pending claims are patentably distinct from claims 1-3 of the '055 Patent in view of Reekie. The claimed compounds demonstrate unexpected benefits that cannot be reasonably expected by a skilled artisan in view of the '055 Patent and Reekie.
As detailed above, ‘055 teaches the core of the biguanid compound with a phenyl rather than a cubanyl of the instant application. Reekie teaches the advantage of a cubanyl substitution of the core compound of ‘055 in place of the phenyl and although Reekie suggests the two compounds performed equivalently; the IC50 comparison of the two molecules showed a 152% increase in activity of the cubanyl substituted molecule over the phenyl group. The only comparative IC50 data provided by the applicant relates to the antiviral activity of both HCB and HBB, but clearly shows IC50 data that is less that 152% increase that Reekie referred to as equivalent to the non cubanyl substituted compound. Therefore, the applicant’s argument is not convincing because either Reekie teaches an advantage of using the cubanyl in place of a phenyl, or does not, but the IC50 data provided by the applicant is less than the IC50 data as detailed by Reekie.
Double Patenting Rejection Reiterated
Claim 2 of the instant application and the claims of ‘055 are identical except for the requirement of a cubanyl-substituted alkyl in claim 2. For example,
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Claim 1 of ‘055 Claim 2 of the instant application
Although the cubanyl compound of claim 2 in the instant application is different from the phenyl group of ‘055, the rest of the compound is identical. Reekie teaches that there is a structure activity relationship between cubane moieties and phenyl groups (e.g. the two functional groups are isosteres).
Claim 11 is drawn to the method of using biguanide molecules of claim 1 of the instant application to treat specific breast cancers including ER+ breast cancer, a HER2+ breast cancer, an ER+ and HER2+ breast, cancer, an ER+ and HER2- breast cancer, or a HER2+ and ER- breast cancer.
Claim 2 of ‘055 identifies a method of treating breast cancer using the biguanide compound to treat breast cancer that is estrogen receptor positive (ER+), human epidermal growth factor receptor 2 (HER2) negative breast cancer.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/P.R.G./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629