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 .
Claims 1, 7-20, 23 and 24 are pending.
Claims 11-20 and 23 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1, 7-10, and 24, drawn to a fentanyl hapten-carrier conjugate that read on (A) CRM, KLH and BSA and GMP grade subunit KLH (sKLH) as the species of immunogenic carrier, (B) toll like receptor agonist as the species of adjuvant, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/932,757, filed November 8, 2019, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 6, 2026 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Objection and Rejection Withdrawn
The objection to claims 3, 6 and 10 is withdrawn in view of the claim amendment.
The rejection of claims 3 and 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn as the claims have been canceled.
The rejection of claims 3 and 10 on the judicially-created basis that they contain an improper Markush grouping of alternatives is withdrawn as the claims have been canceled.
The rejection of claims 1 and 3-5 under 35 U.S.C. 102 (a)(2)as being anticipated by Raleigh et al (of record, J of Pharmacology and Experimental Therapeutics 368: 282-291, February 2019; PTO 892) is withdrawn in view of the amendment to claim 1.
The rejection of claims 1, 2, 21 and 22 under 35 U.S.C. 103 as being unpatentable over Pentel (US20140093525, published April 3, 2014; PTO 892) as evidenced by Raleigh et al (of record, J of Pharmacology and Experimental Therapeutics 368: 282-291, February 2019; PTO 892) and Murad (BioDrugs 23(3): 361-75, 2009; PTO 892) in view of Pravetoni et al (Vaccine 30: 4617-4625, 2012; PTO 892) is withdrawn in light of the claim amendment.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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, 7-10, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
Claim 1 encompasses any fentanyl hapten-carrier conjugate comprising a fentanyl hapten comprising
PNG
media_image1.png
269
379
media_image1.png
Greyscale
any immunogenic carrier comprising any cross-reactive material (CRM), wherein the fentanyl hapten is conjugated to the immunogenic carrier.
Claim 2 encompasses the fentanyl hapten-carrier conjugate of claim 1, wherein the F1 has a differential scanning calorimetry (DSC) thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 110 degrees Celsius (°C) to 130°C;wherein the Fi has a DSC thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 175°C to 185°C; wherein the F1 has a decompensation temperature of at least 200°C, at least 225°C, or at least 250°C, as measured by thermogravimetric analysis (TGA); or wherein the F1 has a haptenation ratio to BSA, of at least 10, at least 15, at least 20; or more than 20; or a combination thereof.
Claim 7 encompasses the fentanyl hapten-carrier conjugate of claim 1, wherein the fentanyl hapten is conjugated to the immunogenic carrier through carbodiimide chemistry.
Claim 8 encompasses a composition comprising the fentanyl hapten-carrier conjugate of claim 1.
Claim 9 encompasses the composition of claim 8, wherein the composition further comprises an adjuvant.
Claim 10 encompasses the composition of claim 9, wherein the adjuvant comprises an aluminum salt-based adjuvant, complete Freund's adjuvant (CFA), incomplete Freund's adjuvant (IFA), a phytol-based adjuvant, a carbohydrate-based adjuvant, a toll like receptor agonist (elected species), a oligomerization domain (NOD)-like receptor (NLR) agonist, a RIG-I-like receptor (RLR) agonist, a C-type lectin receptor (CLR) agonist, degradable nanoparticles, or non-degradable nanoparticles, or combinations thereof.
Claim 24 encompasses the fentanyl hapten of claim 1, wherein the fentanyl hapten is conjugated to the immunogenic carrier through NHS-ester chemistry.
The specification discloses:
[0197] Experiment 1: Efficacy of F-KLH on opioid distribution and antinociception after single s.c. injection of fentanyl in mice. Mice vaccinated with F-KLH had 92±62×10.sup.3 (mean±SD) fentanyl-specific antibody titers. Estimated minimum antibody concentrations were 5.3±1.5 mg/ml. Because of the manner in which this minimum concentration was estimated (from the concentration of fentanyl retained in serum by antibody), actual antibody concentration may have been higher. F-KLH vaccination significantly reduced fentanyl-induced antinociceptive effects on the hotplate by 60% compared to controls (FIG. 2A, p<0.01). Serum fentanyl concentrations were significantly increased in F-KLH vaccinated mice compared to controls (FIG. 2B, p<0.001).
[0198] Experiment 2: Efficacy of F-KLH on opioid distribution and antinociception after single s.c. injection of fentanyl in rats. Rats vaccinated with F-KLH had 9.0±4.4×10.sup.3 fentanyl-specific antibody titers. Estimated minimum antibody concentrations were 18.6±8.5 mg/ml. The molar ratio of the fentanyl dose (0.035 mg/kg) to the estimated antibody binding sites in F-KLH vaccinated rats was 3.2. F-KLH vaccination significantly reduced fentanyl-induced antinociceptive effects on the hotplate by 93% compared to controls (FIG. 3A, p<0.05). F-KLH vaccination had no effect on heroin- or oxycodone-induced antinociception (FIG. 3B and FIG. 3C, p=0.64 and 0.76, respectively). One week after antinociceptive testing, rats received a 1-minute infusion of 0.05 mg/kg i.v. fentanyl. The molar ratio of the fentanyl dose (0.05 mg/kg) to the estimated antibody binding sites in F-KLH vaccinated rats was 4.6. Serum fentanyl concentrations were significantly increased (FIG. 3D, p<0.001) and brain fentanyl concentrations were decreased by 30% (FIG. 3E, p<0.05) compared to controls.
[0199] Experiment 3: Fentanyl-induced antinociception and respiratory depression after cumulative s.c. fentanyl dosing in rats. Latency to respond on the hotplate was significantly increased following the 25, 50, and 100 mg/kg cumulative doses (FIG. 4A, p<0.001 at all three doses) compared to baseline latencies. Naloxone returned latencies to respond on the hotplate back to baseline levels. Percent SaO2 levels were significantly reduced following the 50 and 100 mg/kg cumulative doses (FIG. 4B, p<0.01 and p<0.001, respectively). Naloxone reversed % SaO2 levels to baseline values. Heart rate (in beats per minute) was significantly lowered following the 25, 50, and 100 μg/kg cumulative doses (FIG. 4C, p<0.01 at all three doses). Naloxone treatment did not reverse BPM back to baseline (p<0.001).
[0200] Experiment 4: Efficacy of F-sKLH on opioid distribution, antinociception, and respiratory depressive effects after cumulative s.c. fentanyl dosing in rats. Rats vaccinated with F-sKLH had 25±9.6×10.sup.3 fentanyl-specific antibody titers. Estimated minimum antibody concentrations were 68.2±46 mg/ml. The molar ratio of the fentanyl dose (0.1 mg/kg) to the estimated antibody binding sites in F-sKLH vaccinated rats was 2.5. F-sKLH attenuated fentanyl-induced antinociception by shifting the latency to respond dose-response curve to the right on the hotplate after increasing cumulative doses of fentanyl (FIG. 4D, vaccination, F(1,14)=42.0, p<0.001; interaction, F(5,70)=10.4, p<0.001; fentanyl dose, F(3.35,46.9)=40.9, p<0.001). Fentanyl significantly increased latency to respond following 25 mg/kg in sKLH vaccinated rats, but only after 100 mg/kg in the F-sKLH group, compared to their baseline values. These values represent an ED.sub.50 of 0.02±0.01 mg/kg in the sKLH group and 0.08±0.06 mg/kg in the F-sKLH group, decreasing fentanyl potency by a 5.4-fold shift in the presence of fentanyl-specific antibodies. Naloxone completely reversed fentanyl-induced antinociception in both groups. F-sKLH significantly reduced fentanyl-induced respiratory depression following the 50 mg/kg fentanyl dose and shifted the % SaO2 dose-response curve rightward (FIG. 4E, vaccination, F(1,14)=17.7, p<0.001; interaction, F(5,70)=9.1, p<0.001; fentanyl dose, F(2,28.1)=49.7, p<0.001). Fentanyl significantly decreased % SaO2 following 25 mg/kg in sKLH vaccinated rats, but only after 100 mg/kg in the F-sKLH group, compared to their baseline values. Naloxone completely reversed fentanyl-induced % SaO2 in the F-sKLH vaccinated group, but not in controls (p<0.05). There was no effect of F-sKLH on fentanyl-induced bradycardia (FIG. 4F, vaccination, F(1,14)=2.09, p=0.17; interaction, F(5,70)=3.25, p<0.05; fentanyl dose, F(1.65,23.0)=4.5, p<0.05). However, fentanyl significantly decreased the heart rate in sKLH, but not in F-sKLH, treated rats compared to their baseline (p<0.05). Naloxone completely reversed fentanyl-induced bradycardia in both groups.
[0201] Serum fentanyl concentrations were significantly higher in F-sKLH vaccinated rats compared to controls (p<0.001) following the 100 mg/kg cumulative s.c. fentanyl dose (FIG. 5A). Brain fentanyl concentrations were 73% lower in F-sKLH vaccinated rats compared to controls following the 100 mg/kg cumulative s.c. fentanyl dose (FIG. 5B, p<0.01).
Example 2—A Re-Formulated Fentanyl Vaccine Alters Fentanyl Distribution and
Protects Against Fentanyl-Induced Effects in Mice and Rats
[0212] This Example describes the development of a novel vaccine formulation including a re-formulated F.sub.1 hapten conjugated to the GMP-grade subunit keyhole limpet hemocyanin (sKLH) or to CRM from various sources via an optimized conjugation strategy.
[0213] In this Example, F.sub.1-sKLH, F.sub.1-CRM.sub.1, and F.sub.1-CRM.sub.2 conjugates were characterized for their biophysical properties and then tested in mice and rats (FIG. 6-FIG. 14). Immunized mice and rats were challenged for fentanyl-induced behavior and toxicity commonly associated with opioid use disorders and overdose. Immunization with F.sub.1-CRM.sub.1, and F.sub.1-CRM.sub.2 showed increased efficacy over the previously characterized F.sub.1-sKLH (see Example 1) in blocking fentanyl-induced antinociception (FIG. 8, FIG. 9, FIG. 11), respiratory depression, and bradycardia (FIG. 9, FIG. 11). Vaccination was also effective in reducing sufentanil-induced antinociception (FIG. 10), supporting the use of fentanyl-based vaccines against other potent fentanyl analogs. Vaccination was effective in rats with ongoing fentanyl intravenous self-administration (FSA), as shown by the F.sub.1-CRM.sub.1 ability to reduce FSA (FIG. 12). Furthermore, rats immunized with F.sub.1-CRM.sub.1, discontinued FSA under a dose-reduction protocol supporting the notion that immunization against fentanyl does not cause an increase in FSA to compensate for dose reduction and overcome vaccine efficacy (FIG. 12). Vaccination against fentanyl was equally effective in mice housed in conventional or specific pathogen conditions (FIG. 13) suggesting that the environment or microbiota may not affect vaccine efficacy against fentanyl and other opioids. Moreover, these results suggest that an immunocompromised patient (for example, an HIV.sup.+ patient) may still be benefit from immunization against fentanyl or other opioids. Finally, efficacy of F.sub.1-CRM.sub.1, and to a lesser extent F.sub.1-sKLH, was enhanced by an immunomodulator of the interleukin 4 (IL-4) confirming that IL-4 is either a pharmacological target for enhancing vaccine efficacy against opioids and that IL-4 is a biomarker of vaccine efficacy against fentanyl and other opioids (FIG. 14).
Example 3
[0228] This Example describes further characterization of the re-formulated F.sub.1 hapten (Example 3A-Example 3A) and the re-formulated F.sub.1 hapten conjugated to a carrier (Example 3C). The re-formulated F.sub.1 hapten and the conjugates were prepared as described in Example 2 and Example 5.
Example 3A—Thermogravimetric Analysis (TGA) of F.SUB.1 .Hapten
[0229] TGA Q500 V20.13 Build 39 (TA Analysis, New Castle, Del.) instrument was used to determine the percentage weight loss (%) of the fentanyl hapten F.sub.1 (lyophilized powder) during heating. 1.999 mg of F.sub.1 were heated from 15° C. to 300° C. with a heating rate of 10° C./min and a nitrogen gas purge of 60 mL/min. FIG. 15A shows that F.sub.1 lithium salt contained 4-5% water (w/w) and started decomposing at ˜240° C.
Example 3B—Differential Scanning Calorimetry (DSC) of F.SUB.1 .Hapten
[0230] DSC Q1000 V9.9 Build 303 (TA Analysis, New Castle, Del.) instrument was used to record the DSC thermograms. 12.700 mg of fentanyl hapten F.sub.1 were accurately weighed and sealed in an aluminum hermetic pan, poked on the top to allow for water escape during heating. The sample was heated and cooled three times from 0° C. to 150-200° C. using a heating rate of 20° C./minute and a nitrogen gas purge of 25 mL/minute. The onset temperatures of the thermal events were extrapolated with the TA Universal Analysis software. Results are shown in FIG. 15B. Cycle 1 shows a great endothermic event linked to water desorption. The glass transition temperature (Tg) of the dehydrated F1 sample is shown in Cycle 2 at approximately 120° C. The endothermic peak in Cycle 3 (onset ˜180° C.) is F.sub.1 melting peak.
Example 3C—MALDI-TOF and DSC Analysis of F.SUB.1.-Carrier Conjugate
[0231] MALDI-TOF was performed as described in Baruffaldi et al. Mol. Pharmaceutics 2018; 15(11):4947-4962. DSC was performed as described in Example 3B.
[0232] Results are shown in FIG. 15C-FIG. 15F.
[0233] These data indicate that F.sub.1 conjugated to different carriers may have a different physical chemical profile. For example, F.sub.1 behaves differently when attached to sKLH, or different CRM versions, as assessed by MALDI-TOF and DLS for MW and size or aggregation state.
[0234] In addition, these data indicate that F.sub.1-sKLH is not stable overtime because its peak shifted in size from T=0 to T=1 month. In contrast, F.sub.1-CRM.sub.1, and F.sub.1-CRM.sub.2 were stable for at least 1 month.
[0235] Further, as shown by the size of F.sub.1-CRM.sub.1, and F.sub.1-CRM.sub.2 (as assessed by either DLS or MALDI-TOF), these conjugates can be sterile filtered by 0.45 nm or 0.22 nm pore-size filters. In contrast, F.sub.1-sKLH cannot be analyzed by MALDI-TOF nor sterile filtered because of its high molecular weight and aggregation status.
Example 4
[0236] This Example describes further testing of the vaccine formulation including re-formulated F.sub.1 hapten conjugated to CRM, prepared as described in Example 2 and Example 5.
Example 4A—Pre-Existing Immunity Against Carrier Proteins do not Interfere with Vaccination Against Fentanyl
[0237] Because it is likely that human subjects have been previously exposed to common carrier proteins through standard pediatric or occupational immunization (for example, diphtheria or tetanus prophylaxis), whether pre-exposure to carrier proteins would interfere with vaccination was tested. A similar study previously found that pre-existing immunity to carrier proteins may affect the efficacy of anti-nicotine vaccines (McCluskie et al., Immunopharmacol Immunotoxicol. 2016; 38(3):184-96).
[0238] Mice were first immunized i.m. on day −14 with either saline control or 60 μl of carrier protein, then immunized using the corresponding F.sub.1-carrier protein conjugate on days 0, 14 and 28. Pre-exposure to either sKLH or CRM.sub.2 had no effect on fentanyl-specific serum IgG antibody titers, while pre-exposure to CRM.sub.1 negatively impacted development of fentanyl-specific antibody titers (FIG. 16).
[0239] These data indicate that both sKLH and CRM.sub.2 are viable carrier proteins for future vaccine development as pre-exposure in animals did not significantly diminish vaccine efficacy. In addition, these date show 1) vaccination with F.sub.1-CRM did not interfere with pharmacological activity of commonly used anesthetics (FIG. 17); and 2) vaccination with F.sub.1-CRM did not interfere with pharmacological activity of opioid agonists, and antagonists used in treatment of opioid use disorders, overdose reversal, or pain management (FIG. 18).
Example 4B—Vaccination Against Fentanyl does not Interfere with Anesthesia
[0240] To provide proof of safety and to guide clinical use of anti-fentanyl vaccines, it is critical to identify lead vaccines that do not interfere with medications for OUD, standard critical care, and pain management. To determine whether anti-fentanyl vaccines would interfere with anesthesia, rats were immunized with either CRM.sub.1 or F.sub.1-CRM.sub.1 and then challenged weekly with a series of anesthetics. Anesthetic efficacy was measured by respiratory depression and bradycardia. Vaccination with F.sub.1-CRM.sub.1 did not interfere with anesthesia induced by dexmedetomidine (0.25 mg/kg, FIG. 17A-FIG. 17C), and did not prevent its reversal by the standard dexmedetomidine-reversal agent atipamezole (1 mg/kg). Accordingly, no differences between control and active vaccine groups were found when rats were anesthetized with ketamine (75 mg/kg, FIG. 17D-FIG. 17E), propofol (100 mg/kg, FIG. 17F), or isoflurane (FIG. 17G-FIG. 17H). Following multiple challenges with anesthetics, the F.sub.1-CRM vaccinated rats retained efficacy against fentanyl (0.05 mg/kg, FIG. 17I-FIG. 17K). These data demonstrate that F.sub.1-CRM.sub.1 is selective for fentanyl and does not interfere with commonly used anesthetics.
Example 4C—Vaccination Against Fentanyl does not Interfere with the Pharmacological Activity of Agonists and Antagonists
[0243] To test whether anti-fentanyl vaccines would interfere with opioid receptor agonists and antagonists used in treatment of OUD and pain management, rats were immunized with either CRM.sub.1 or F.sub.1-CRM.sub.1 and challenged weekly with a series of agonists or antagonists. Efficacy of opioids was measured by antinociception on the hotplate. In this experiment, rats were challenged sequentially with either oxycodone (2.25 mg/kg, s.c.) or heroin (0.9 mg/kg, s.c.), and antinociception was measured 30 minutes post-challenge. Immediately after, rats were given naloxone (0.1 mg/kg, s.c.) to reverse opioids' effects. Vaccination with F.sub.1-CRM.sub.1 did not interfere with antinociception induced by either oxycodone (FIG. 18A, FIG. 18C) or heroin (FIG. 18B, FIG. 18D), and did not impact the efficacy of naloxone in reversing either oxycodone or heroin effects (FIG. 18A-FIG. 18D). Next, rats were challenged with methadone (2.25 mg/kg, s.c.) and showed that methadone-induced antinociception was not different between CRM.sub.1 and F.sub.1-CRM.sub.1 (FIG. 8E). As a positive control, a final challenge with fentanyl (0.1 mg/kg, s.c.) confirmed that the efficacy of F.sub.1-CRM.sub.1 was preserved against its target opioid (FIG. 18F). These data indicate that vaccination with F.sub.1-CRM.sub.1 does not interfere with the pharmacological activity of oxycodone and methadone, as well as naloxone reversal of the effects of oxycodone and heroin.
[0244] In vivo data were further supported by in vitro competitive binding studies demonstrating that polyclonal antibodies induced by conjugates containing the F.sub.1 hapten did not cross-react with methadone, buprenorphine, naltrexone, and naloxone (Table 2C). Hence, it is expected that clinical implementation of vaccines will not impact use of current medications for OUD.
Example 4D—Vaccination with F.SUB.1.-Containing Conjugates May Protect from Fatal Overdose from Fentanyl and its Analogs
[0245] To determine whether the F.sub.1-CRM.sub.2 conjugate could protect against lethal overdose of fentanyl, a cumulative dosing regimen was administered. Rats were vaccinated i.m. on days 0, 21, 42 and 63 with either F.sub.1-CRM.sub.2 or unconjugated carrier protein. Tail blood was collected on day 69. On day 76, rats were allowed to acclimate to the testing environment for 1 hour, followed by a baseline measurement of oximetry using a MouseOx Plus pulse oximeter (Starr Life Sciences, Oakmont, Pa.). Rats were then given 0.25 mg/kg s.c. fentanyl every 15 minutes to a maximum cumulative dose of 2.25 mg/kg. Prior to each successive dose, rats were measured on the oximeter for respiratory depression and bradycardia. Rats that displayed cardiac or respiratory arrest during the testing period were promptly euthanized via CO.sub.2 and blood and brain were collected for LCMS. If the animal did not go into cardiac or respiratory arrest, a final measurement was taken 15 minutes after the final cumulative dose of 2.25 mg/kg and blood and brain were then collected for LCMS.
[0246] Results are shown in FIG. 19.
[0247] These results show the vaccine was effective against opioid-induced respiratory depression, bradycardia, and fatal overdose during cumulative fentanyl dosing.
Example 4E—Efficacy of Vaccines Containing the F.SUB.1 .Hapten Against Acetylfentanyl in Rats
[0248] To test the efficacy of vaccines including the F.sub.1 hapten against acetylfentanyl, rats were immunized with control or with F.sub.1-CRM.sub.2 and then were challenged with acetylfentanyl. Results are shown in FIG. 20 ns indicate that vaccination using F.sub.1-CRM.sub.2 may be protective against opioid-induced respiratory depression and bradycardia during cumulative acetylfentanyl dosing.
Example 5
[0249] This Example provides additional information regarding the synthesis of fentanyl hapten F.sub.1, according to Scheme 2 (FIG. 1D).
Other than fentanyl hapten-carrier conjugate comprising fentanyl hapten F1 having the structure shown in claim 1 conjugated to the GMP-grade subunit keyhole limpet hemocyanin (sKLH) or to cross-reactive material (CRM) from diphtheria toxin, the specification does not describe the structure-identifying information about the claimed immunogenic carrier conjugated to any fentanyl hapten F1 that correlated with having a differential scanning calorimetry (DSC) thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 110 degrees Celsius (°C) to 130°C; or wherein the F1 has a DSC thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 175°C to 185°C; wherein the F1 has a decompensation temperature of at least 200°C, at least 225°C, or at least 250°C, as measured by thermogravimetric analysis (TGA); or wherein the F1 has a haptenation ratio to BSA, of at least 10, at least 15, at least 20; or more than 20; or a combination thereof.
The specification does not describe a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed fentanyl hapten-carrier conjugate themselves.
Regarding “CRM” as the immunogenic carrier in claim 1, the function of immunogenic to the claimed fentanyl hapten-carrier conjugate does not distinguish a particular “CRM" from others having the same activity or function and as such, fails to satisfy the written-description requirement. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Structural features that could distinguish a “CRM” in the genus from others in the protein class are missing from the disclosure and the claims. No common structural attributes identify the members of the genus. The general knowledge and level of skill in the art do not supplement the omitted description, because specific, not general guidance is needed. Since the disclosure does not describe the common attributes or structural characteristics that identify members of the genus, and because the genus is highly variant, the function of immunogenic alone is insufficient to describe the genus of “CRM” polypeptides of that function equivalently. One of skill in the art would reasonable conclude that the disclosure of a cross-reactive material (CRM) from diphtheria toxin, does not provide a representative number of species of CRM describe the claimed genus. Amending claim 1 to cross-reactive material (CRM) from diphtheria toxin would obviate this issue.
Regarding adjuvant comprises any degradable nanoparticles or non-degradable nanoparticles of a combination thereof (claim 10), the specification discloses adjuvant is an aluminum salt-based adjuvant,
complete Freund's adjuvant (CFA), incomplete Freund's adjuvant (IFA), a phytol-based adjuvant, a carbohydrate-based adjuvant, a toll like receptor agonist (elected species), a oligomerization domain (NOD)-like receptor (NLR) agonist, a RIG-I-like receptor (RLR) agonist, a C-type lectin receptor (CLR) agonist, see para. [0073].
However, there is no objective of evidence of any degradable nanoparticles, or non-degradable nanoparticles, or combinations thereof are immunogenic in the specification or the claims as filed. They are simply carrier.
As such, one skilled in the art would not recognize that applicants had possession of the genus of claimed fentanyl hapten-carrier conjugate comprising the structure as set forth in claim 1 and any immunogenic carrier at the time of filing.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only (1) a fentanyl hapten-carrier conjugate comprising a fentanyl hapten comprising
PNG
media_image1.png
269
379
media_image1.png
Greyscale
an immunogenic carrier, wherein the fentanyl hapten is conjugated to the immunogenic carrier, wherein the immunogenic carrier is cross-reactive material (CRM) from diphtheria toxin, (2) Said fentanyl hapten-carrier conjugate wherein the fentanyl hapten is conjugated to the immunogenic carrier through carbodiimide chemistry, (3) a composition comprising said fentanyl hapten-carrier conjugate and an adjuvant, (4) the composition wherein said adjuvant is selected from the group consisting of an aluminum salt-based adjuvant, complete Freund's adjuvant (CFA), incomplete Freund's adjuvant (IFA), a phytol-based adjuvant, a toll like receptor agonist (elected species), and a combination thereof, (5) the fentanyl hapten-carrier conjugate wherein the F1 has a haptenation ratio to BSA of at least 20 or a haptenation ration to CRM1 of at least 18, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicants’ arguments filed January 6, 2026 have been fully considered but are not found persuasive.
Applicants’ position is that claim 1 has been amended to recite claim 1 recites a fentanyl hapten-carrier conjugate including cross-reactive material (CRM) as the immunogenic carrier.
Applicant requests that the Examiner consider the disclosures of the specification at, for instance, page 53, lines 15-20; page 54, lines 3-20; and Table 1, page 58, lines 1-4, which expressly disclose individual species of CRM that were conjugated to the fentanyl hapten.
In response, the amendment to the claim 1 is acknowledged. The specification discloses cross-reactive material (CRM) from just diphtheria toxin, see page 53, lines 15-20. However, the amended claim 1 recites any reactive material (CRM). Applicant has not described any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function, e.g., immunogenic is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Structural features that could distinguish a “CRM” in the genus from others in the protein class are missing from the disclosure and the claims. No common structural attributes identify the members of the genus. The general knowledge and level of skill in the art do not supplement the omitted description, because specific, not general guidance is needed. Since the disclosure does not describe the common attributes or structural characteristics that identify members of the genus, and because the genus is highly variant, the function of immunogenic alone is insufficient to describe the genus of “CRM” polypeptides of that function equivalently. One of skill in the art would reasonable conclude that the disclosure of a cross-reactive material (CRM) from diphtheria toxin, does not provide a representative number of species of CRM describe the claimed genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed cross-reactive material (CRM) themselves.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For these reasons, the rejection is maintained.
Note, amending claim 1 to cross-reactive material (CRM) from diphtheria toxin would obviate this rejection.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 and 7-10 are rejected under 35 U.S.C. 102 (a)(1) or (a)(2) as being anticipated by Pentel (US20140093525, published April 3, 2014; PTO 892) as evidenced by Raleigh et al (of record, J of Pharmacology and Experimental Therapeutics 368: 282-291, February 2019; PTO 892) and Murad (BioDrugs 23(3): 361-75, 2009; PTO 892).
PNG
media_image2.png
435
825
media_image2.png
Greyscale
Regarding claim 1, Pentel teaches hapten-carrier conjugate, e.g., hapten-X-Z wherein the hapten is fentanyl, X is a linker, e.g., (Gly)4, and Z is an antigen carrier molecule, e.g., KLH or see para. [0051], [0054], claims 11-15, 17, Fig. 15, in particular.
Evidentiary reference Raleigh teaches that the entanyl(Gly)4-KLH inherently comprises the claimed structure:
PNG
media_image3.png
297
345
media_image3.png
Greyscale
wherein (Gly)4 has the structure
PNG
media_image4.png
245
225
media_image4.png
Greyscale
, see Pentel reference Fig. 4.
Pentel teaches useful immunogenic proteins include keyhole limpet hemocyanin (KLH), human gamma globulin, chicken immunoglobulin G, bovine gamma globulin, tetanus toxin or toxoid, diphtheria toxin or toxoid, mutant of diphtheria toxin CRM 197 (aka cross-reactive material from diphtheria toxin as evidenced in the specification at p. 53, lines 18-20), pseudomonas exotoxin A, cholera toxin or toxoid, Group A streptococcal toxins, pneumolysin of Streptococcus pneumoniae, filamentous haemagglutinin (FHA), FHA fragments of Bordetella pertussis; pili or pilins of Neisseria gonorrhoeae, pili or pilins of Neisseria meningitidis; outer membrane proteins of Neisseria meningitidis, outer membrane proteins of Neisseria gonorrhoeae; C5A peptidase of Streptococcus or a surface protein of Moraxella catarrhalis, see para. [0058], [0085], reference claim 6. Hapten was also conjugated to KLH, because KLH is suitable for administration to humans, whereas BSA is not, see para. [0102].
Pentel further teaches various conjugate haptenation ratios wherein the F1 has a haptenation ratio to BSA of 16, which is at least 10 or at least 15, see Table 1, in particular.
PNG
media_image5.png
202
308
media_image5.png
Greyscale
Regarding claim 7, Pentel teaches that the hapten is conjugated to the immunogenic carrier through carbodiimide chemistry, see para. [0077], [0078], [0085].
Regarding claims 8-9, Pentel teaches vaccine composition comprising the reference hapten-carrier conjugate, see para. [0063] to [0064]. The composition comprises an adjuvant, e.g., alum or monophosphoryl lipid A (MPLA) can be used in certain embodiments. Suitable adjuvants include but are not limited to surfactants, e.g., hexadecylamine, octadecylamine, lysolecithin, dimethyldioctadecylammonium bromide, N,N-dioctadecyl-N'--N-bis(2-hydroxyethyl-propane di-amine), methoxyhexadecyl-glycerol, and pluronic polyols; polanions, e.g., pyran, dextran sulfate, poly IC, polyacrylic acid, carbopol; peptides, e.g., muramyl dipeptide, aimethylglycine, tuftsin, oil emulsions, alum, and mixtures thereof. Other potential adjuvants include the B peptide subunits of E. coli heat labile toxin or of the cholera toxin, or CpG oligonucleotides (a known Toll-like receptor 9 agonist), See para. [0060]. Evidentiary reference Murad (BioDrugs 23(3): 361-75, 2009, abstract) teaches TLR9, recognizes unmethylated CpG (cytosine guanosine dinucleotide), abstract, in particular.
Regarding claim 10, Pentel teaches vaccine composition comprising incomplete Freund’s adjuvant, see para. [0087].
Claim 2 is include because Products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties, e.g., a differential scanning calorimetry (DS) thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 110 degrees Celsius to 130 degree C, or a decompensation temperature of at least 200 ˚C, applicant discloses and/or claims are necessarily present. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.
Thus, the reference teachings anticipate the claimed invention.
Applicants’ arguments filed January 6, 2026 have been fully considered but are not found persuasive.
Applicants’ position is that claim 1 has been amended to recite claim 1 recites a fentanyl hapten-carrier conjugate including cross-reactive material (CRM) as the immunogenic carrier.
"A claim is anticipated only if each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference."Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987); M.P.E.P. § 2131.
Pentel does not disclose a fentanyl hapten-carrier conjugate including cross-reactive material (CRM).
In response, the amendment to the claim 1 is acknowledged. Contrary to applicant’s assertion, Pentel does not disclose cross-reactive material (CRM), Pentel teaches the claimed mutant of diphtheria toxin CRM 197, aka cross-reactive material (CRM) from diphtheria toxin as evidenced in the specification at p. 53, lines 18-20. Pentel exemplifies fentanyl hapten-carrier conjugate to immunogenic carrier, including but not limited to KLH, cross-reactive material (CRM). Pentel teaches useful immunogenic proteins include keyhole limpet hemocyanin (KLH), human gamma globulin, chicken immunoglobulin G, bovine gamma globulin, tetanus toxin or toxoid, diphtheria toxin or toxoid, see para. [0058], [0085], reference claim 6.
For these reasons, the rejection is maintained.
New ground of rejection necessitated by the amendment filed January 6, 2026
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Pentel (US20140093525, published April 3, 2014; PTO 892) as evidenced by Raleigh et al (of record, J of Pharmacology and Experimental Therapeutics 368: 282-291, February 2019; PTO 892) and Murad (BioDrugs 23(3): 361-75, 2009; PTO 892) in view of Nakaar et al (US20100303847, newly cited, published December 2, 2010; PTO 892) and Hott et al (US20020081303, newly cited, published June 27, 2002; PTO 892).
The teachings of Pentel as evidenced by Raleigh and Murad have been discussed supra.
The references above do not teach the fentanyl hapten is conjugated to immunogenic carrier through NHS-ester chemistry as per claim 24.
However, Nakaar teaches different chemistry can be employed to conjugate Toll-like Receptor agonist components of nucleic acid TLRs to HPV protein components. For example, amine-modified nucleic acid can then be conjugated to a lysine using NHS-ester, see para. [0132]. Immunogenic carriers include Tetanus toxoid (TT), Vibrio cholerae toxoid, Diphtheria toxoid (DT), a cross-reactive mutant (CRM) of diphtheria toxoid, see para. [0214].
Hott teaches SPDP is a reversible NHS-ester, a common and versatile class of amine-reactive crosslinker for protein conjugation; SMPT is another reversible NHS-ester. Additionally, the NHS-ester of SMPT is relatively stable in aqueous solutions.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to conjugate or crosslink Pentel’s fentanyl hapten to a carrier protein such as a cross-reactive mutant (CRM) of diphtheria toxoid by substituting Pentel’s carbodiimide chemistry of Pentel with Nakaar’s or Hott’s NHS-ester chemistry to arrive at the claimed invention with a reasonable expectation of success, e.g., fentanyl hapten-carrier conjugated to an immunogenic carrier comprising a cross-reactive mutant or material of diphtheria toxoid via amine on the side-chain of lysine amino acid residue.
One of ordinary skill in the art would have been motivated to do so because Hott teaches that
SMPT is a reversible NHS-ester and is relatively stable in aqueous solutions.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
/PHUONG HUYNH/ Primary Examiner, Art Unit 1641