DETAILED ACTION
Status of the Application
Receipt is acknowledged of Applicants’ Amendments and Remarks, filed 16 March 2026, in the matter of Application N° 18/222,775. Said documents have been entered on the record. The Examiner further acknowledges the following:
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim 7 has been canceled and its limitations amended into independent claims 1 and 17.
Claims 1 and 17 have been additionally amended to recite that the nanoparticles target polycystic kidney disease. Support for this amendment is found in original claim 14. Claim 8 has been amended to depend from claim 1 and claim 19 has been amended to overcome the previously raised objection.
No claims have been added. No new matter has been added.
Thus, claims 1-6 and 8-20 now represent all claims currently under consideration.
Information Disclosure Statement
One new Information Disclosure Statements (IDS) filed 16 March 2026 is acknowledged and has been considered.
Withdrawn Objections/Rejections
Objections to the Specification/claims
Applicants’ amendment to the instant specification and to claim 19 are both persuasive in overcoming the previously raised objections. Said objections are withdrawn.
Rejection under 35 USC 103
Applicants’ amendment to claim 17 is persuasive in overcoming the obviousness rejection over Zhang et al., alone, but only in part. Claim 17 is directed to a method of targeting one or more pharmaceutical agents to an organ and by amendment, recites targeting polycystic kidney disease. Zhang on its own does not specify targeting this disease. As such, the rejection is only withdrawn over claims 17-20.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 16 December 2025 since the art that was previously cited continues to read on the amended and previously recited limitations.
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 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 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. Applicants are 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 1-4, 8, 9, 13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (CN 105944109(A); machine translation attached and cited). [emphasis added to reflect claims overcome in the response]
The instantly claimed composition is directed to a nanoparticulate formulation comprising one or more pharmaceutical agents that are encapsulated in a triblock copolymer and wherein the nanoparticles target polycystic kidney disease. [emphasis added to reflect amended language] Claim 13 recites a method of treating a chronic kidney disease comprising the administration of the aforementioned nanoparticulate formulation.
Zhang discloses a glomerulus-targeted nanoparticle pharmaceutical composition that is used to treat various kidney diseases, such as primary and secondary glomerulonephritis, which are leading causes of chronic renal failure (see e.g., claims 1-3 and ¶[0004]; ¶[0045]).
The practiced nanoparticle drug composition is taught as comprising one or more pharmaceutically active substance and stabilizers (see e.g., claim 1). Claim 3 further defines the pharmaceutically active substance(s) as including rapamycin and the stabilizer(s) as including poloxamer 188.
Paragraph [0037] discloses that the practiced composition may contain additional excipients such as antioxidants.
The foregoing is considered to teach the compositional limitations recited by instant claims 1-4 and 7-9.
The reference is also considered to teach the limitations of method claims 13 and 15. Regarding claim 15, the reference discloses administering the practiced compositions every other day, and further motivates the skilled artisan to observe a less frequent administration regimen. The reduced frequency is attributed to the nanoparticle having high drug loading and high encapsulation efficiency, which greatly reduces the therapeutic dose of the drug. See ¶[0017] and ¶[0129]-¶[0136].
Based on the foregoing teachings of the reference, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success at producing the instantly claimed composition and arriving at the recited method of treatment. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Response to Arguments
Applicants’ arguments with regard to the rejection of claims 1-4, 8, 9, 13, and 15 under 35 USC 103(a) as being unpatentable over the combined teachings of Zhang et al. have been fully considered, but they are not persuasive.
Applicants traverse the rejection on the grounds that Zhang fails to teach or suggest the limitations of claim 1, as amended. Specifically, Applicants discuss the different conditions that Zhang does teach treating and that Zhang’s disclosure of poloxamer 188 is not a triblock copolymer, but instead a monoblock copolymer.
The Examiner, in response, respectfully disagrees. Addressing the latter assertion first, the Examiner submits that a person of ordinary skill in the pharmaceutical arts readily understands that poloxamers are empirically defined as being triblock copolymers. Poloxamer 188 (aka Pluronic® F-68) is a polyethylene oxide-polypropylene oxide- polyethylene oxide triblock copolymer having the formula: PEOa-PPOb-PEOa, where ‘a’ is about 80, and ‘b’ is about 30.
Addressing the initial ‘targeting’ assertion, the Examiner submits that this new language is considered to be drawn to an intended use of the composition that is at issue. Furthermore, the newly presented language does not narrow the scope of the claimed composition. Therein, it does not further limit the composition as instantly recited (i.e., it does not set forth the metes and bounds of the one or more pharmaceutical agent(s)).
Applicants’ arguments, for the above reasons, are found unpersuasive over the remaining claims of the rejection. Said rejection is therefore maintained.
Claims 1-4, 8-11, 13-15, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (CN 105944109(A); machine translation attached and cited) in view of Kipp et al. (Am J Physiol Renal Physiol; 2018). [emphasis added to reflect canceled claim]
The limitations recited by claims 1-4, 8, 9, 13, 15, and 17-20 are discussed above.
Zhang discloses a glomerulus-targeted nanoparticle pharmaceutical composition that is used to treat various kidney diseases, such as primary and secondary glomerulonephritis, which are leading causes of chronic renal failure (see e.g., claims 1-3 and ¶[0004]; ¶[0045]).
The practiced nanoparticle drug composition is taught as comprising one or more pharmaceutically active substance and stabilizers (see e.g., claim 1). Claim 3 further defines the pharmaceutically active substance(s) as including rapamycin and the stabilizer(s) as including poloxamer 188.
Paragraph [0037] discloses that the practiced composition may contain additional excipients such as antioxidants.
The foregoing is considered to teach the compositional limitations recited by instant claims 1-4 and 7-9.
The reference is also considered to teach the limitations of method claims 13 and 15. Regarding claim 15, the reference discloses administering the practiced compositions every other day, and further motivates the skilled artisan to observe a less frequent administration regimen. The reduced frequency is attributed to the nanoparticle having high drug loading and high encapsulation efficiency, which greatly reduces the therapeutic dose of the drug. See ¶[0017] and ¶[0129]-¶[0136].
The foregoing is also considered to teach the limitations of the method recited by instant claims 17-20. As discussed above, Zhang discloses a glomerular-targeting nanoparticle composition which comprises rapamycin and poloxamer 188. The term “glomerular” is understood by persons of skill in the art as referring to the glomerulus, which is a tiny cluster of blood vessels within in the kidneys that operate as the primary filter for the blood.
Where Zhang is seemingly deficient is that it does not specifically disclose that the method or compositions practiced therein are used to target polycystic kidney disease (claim 14) or that administered composition comprises folate-conjugated rapamycin (claims 10 and 11).
Kipp is considered to supplement the teachings of Zhang and guide the ordinarily skilled artisan towards not only formulating the practiced nanoparticles with rapamycin, but also using the folate-conjugated form.
Therein, the journal article published by Kipp reports on a comparison of folate-conjugated rapamycin (aka FC-rapa) to unconjugated rapamycin with respect to treating polycystic kidney disease (see e.g., Title; Abstract). Highlights of the article disclose that “Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models.” “Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in patients. To overcome this problem, [the authors] previously demonstrated that folate-conjugated rapamycin (FC-rapa) target polycystic kidneys due to the high expression of the folate receptor (FRα) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth.” (See Abstract).
What is demonstrated by the comparison of the conjugated and unconjugated forms is that FC-rapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in the mouse model. Though it is discussed that the overall effectiveness of both forms is relatively indistinct, FC-rapa lacks the undesirable extrarenal effects often encountered with the administration of the unconjugated form.
What this conveys to the ordinarily skilled artisan is that in view of the added teachings offered by Kipp, motivation is present for said artisan to not only select rapamycin from the list of pharmaceutically active ingredients disclosed by Zhang, but also to further conjugate it to folate as instantly claimed.
As presented by both references rapamycin is established as an agent that is used to treat kidney diseases in a targeted fashion. However, Kipp elaborates on the disclosure of rapamycin, explaining that it is already well-known and established to treat more specific diseases such as polycystic kidney disease. Additionally, it is understood that conjugating it folate enhances the targeting of the agent to reduce the likelihood of undesired extrarenal effects.
Thus, based on the foregoing teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success at producing the instantly claimed composition and arriving at the recited methods of treatment. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Response to Arguments
Applicants’ arguments with regard to the rejection of claims 1-4, 8-11, 13-15, and 17-20 under 35 USC 103(a) as being unpatentable over the combined teachings of Zhang et al. and Kipp et al. have been fully considered, but they are not persuasive.
Applicants’ initial traversal of the rejection is on the grounds that Kipp, like Zhang, fails to teach or suggest the use of a triblock copolymer as instantly claimed, with Kipp making no mention of a copolymer.
The Examiner, in response, respectfully submits that this argument is not persuasive for two reasons. First, as discussed above, Zhang does irrefutably teach and suggest the use of a triblock copolymer (i.e., poloxamer 188). Secondly, as addressed in the above rejection, the teachings of Kipp are not relied upon to reconcile the polymer. Instead, they are presented as supporting evidence to Zhang’s disclosure of rapamycin, and when considered in combination by a person of skill in the art, the teachings present a showing of why said artisan would be motivated to modify Zhang to select rapamycin or a derivative of it. The Examiner maintains that the combined teachings provide motivating disclosure to select rapamycin in order to treat polycystic kidney disease as recited in claims 14 and 17.
Lastly, Applicants argue that Zhang’s formulation contains albumin stabilized by a “monoblock” poloxamer 188. The “monoblock” mischaracterization will not be further discussed.
Applicants also argue that “albumin cannot pass beyond the glomerulus due to a combined charge-based and size-selective barrier mechanism within the glomerular filtration membrane. Nanoparticles containing albumin are repelled by the negatively charged glycocalyx on the endothelium and are too large to pass through the slit pores.”
The Examiner, in response, is respectfully unclear as to what teachings in Zhang provide basis for the above opinion.
The Examiner notes that Zhang discloses the following:
“Glomerular mesangial tissue is a special mesenchyme located between glomerular capillary loops, composed of mesangial cells and mesangial matrix, and only porous endothelial cells are separated from the capillaries. The pores of the cells are about 80nm-170nm. In addition, according to literature reports, the effective interception size of nanoparticles by glomerular filtration membrane is about 10nm. Therefore, theoretically speaking, nanoparticles with a particle size of 10nm-170nm flowing through glomerular capillaries can pass through endothelial cells. The pores enter the glomerular mesangium to achieve the targeting effect of the glomerular mesangial cells”
and
“The glomerulus-targeted protein nanoparticle pharmaceutical composition of the present invention, the protein nanoparticle pharmaceutical composition containing pharmacologically active substances and proteins has a particle size between 10nm and 170nm, which can be absorbed by the glomerulus when flowing through the glomerulus The effective retention of the glomerular filtration membrane allows it to enter the glomerular mesangium through the pores (80-170nm) of the glomerular endothelial cells.” [emphases added]
The Examiner, in response, respectfully submits that the reference appears to teach that the pores of the glomerular tissue range from about 80-170 nm and that the size of the practiced particles ranges from 10-170 nm. Based on these dimensions, the reference further appears to teach that some particles flowing into and through the glomerulus will be retained while others will pass through.
Regarding the argument that Zhang’s nanoparticles contain albumin, the Examiner respectfully submits that the scope of the instantly claimed inventions does not exclude albumin from it.
Applicants’ arguments, for the above reasons, are found unpersuasive. Said rejection is therefore maintained.
Claims 1-6 and 8-20 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (CN 105944109(A); machine translation attached and cited) in view of Kipp et al. (Am J Physiol Renal Physiol; 2018) and further in view of Knight et al. (J. Am. Soc. Nephrol.; 2012). [emphasis added to reflect canceled claim]
The limitations recited by claims 1-4, 8, 9, 13, 15, and 17-20 are discussed above.
Zhang discloses a glomerulus-targeted nanoparticle pharmaceutical composition that is used to treat various kidney diseases, such as primary and secondary glomerulonephritis, which are leading causes of chronic renal failure (see e.g., claims 1-3 and ¶[0004]; ¶[0045]).
The practiced nanoparticle drug composition is taught as comprising one or more pharmaceutically active substance and stabilizers (see e.g., claim 1). Claim 3 further defines the pharmaceutically active substance(s) as including rapamycin and the stabilizer(s) as including poloxamer 188.
Paragraph [0037] discloses that the practiced composition may contain additional excipients such as antioxidants.
The foregoing is considered to teach the compositional limitations recited by instant claims 1-4 and 7-9.
The reference is also considered to teach the limitations of method claims 13 and 15. Regarding claim 15, the reference discloses administering the practiced compositions every other day, and further motivates the skilled artisan to observe a less frequent administration regimen. The reduced frequency is attributed to the nanoparticle having high drug loading and high encapsulation efficiency, which greatly reduces the therapeutic dose of the drug. See ¶[0017] and ¶[0129]-¶[0136].
The foregoing is also considered to teach the limitations of the method recited by instant claims 17-20. As discussed above, Zhang discloses a glomerular-targeting nanoparticle composition which comprises rapamycin and poloxamer 188. The term “glomerular” is understood by persons of skill in the art as referring to the glomerulus, which is a tiny cluster of blood vessels within in the kidneys that operate as the primary filter for the blood.
Where Zhang is seemingly deficient is that it does not specifically disclose that the method or compositions practiced therein are used to target polycystic kidney disease (claim 14) or that administered composition comprises folate-conjugated rapamycin (claims 10 and 11).
Kipp is considered to supplement the teachings of Zhang and guide the ordinarily skilled artisan towards not only formulating the practiced nanoparticles with rapamycin, but also using the folate-conjugated form.
Therein, the journal article published by Kipp reports on a comparison of folate-conjugated rapamycin (aka FC-rapa) to unconjugated rapamycin with respect to treating polycystic kidney disease (see e.g., Title; Abstract). Highlights of the article disclose that “Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models.” “Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in patients. To overcome this problem, [the authors] previously demonstrated that folate-conjugated rapamycin (FC-rapa) target polycystic kidneys due to the high expression of the folate receptor (FRα) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth.” (See Abstract).
What is demonstrated by the comparison of the conjugated and unconjugated forms is that FC-rapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in the mouse model. Though it is discussed that the overall effectiveness of both forms is relatively indistinct, FC-rapa lacks the undesirable extrarenal effects often encountered with the administration of the unconjugated form.
What this conveys to the ordinarily skilled artisan is that in view of the added teachings offered by Kipp, motivation is present for said artisan to not only select rapamycin from the list of pharmaceutically active ingredients disclosed by Zhang, but also to further conjugate it to folate as instantly claimed.
As presented by both references rapamycin is established as an agent that is used to treat kidney diseases in a targeted fashion. However, Kipp elaborates on the disclosure of rapamycin, explaining that it is already well-known and established to treat more specific diseases such as polycystic kidney disease. Additionally, it is understood that conjugating it folate enhances the targeting of the agent to reduce the likelihood of undesired extrarenal effects.
Regarding the limitations of instant claims 4-6, the Examiner acknowledges that despite Zhang disclosing the inclusion of antioxidants in the practiced nanoparticulate compositions, it neither names any particular antioxidants that may be used nor does it define them as being used for anything beyond an excipient component.
Despite this gap in teaching, the Examiner submits that a person of skill in the art in view of the teachings of Knight, would have had motivation to modify the Zhang composition to include more specific antioxidants such as 4-hydroxy-Tempo conjugated with folate (aka tempol-folate).
The Examiner acknowledges that the article is directed to the study of a different kidney disease (i.e., renal ischemia-reperfusion injury). However, the treatment of the disease is of interest and relevant to the instant invention as it embraces the same directed approach as Kipp, namely the targeting of folate receptor-α expression which is found within the proximal tubule (see e.g., Abstract; pg. 794, right col.). What facilitates this is the ability to target therapy to the alpha receptor by conjugating the active ingredient of interest: 4-hydroxy-Tempo. Like Kipp, Knight discloses that without selective targeting, the kidney would require extremely high doses to achieve effective local concentrations of drug. These high concentrations lead to a local increase in superoxide which contributes to renal ischemic injury. What is reported is that conjugated tempol retains its efficacy to scavenge superoxide in the proximal tubule cells, thereby reducing the likelihood of renal ischemic injury. The article, in view of the achieved results, also postulates that other pharmaceuticals conjugated to folate may also facilitate the treatment of other kidney diseases (see e.g., Abstract).
Thus, based on the foregoing teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success at producing the instantly claimed composition and arriving at the recited methods of treatment.
The disclosure of Zhang teaches encapsulated nanoparticulate compositions comprising an active (i.e., rapamycin), a stabilizer (i.e., polymer: poloxamer 188), and an antioxidant. The practiced compositions are taught as being used to treat non-specific glomerular kidney diseases. Each of Kipp and Knight respectively disclose folate-conjugated rapamycin and folate-conjugated 4-hydroxy-tempol. Though the two references rely on the folate conjugated active and antioxidant to treat a different kidney condition, both references disclose that the folate conjugation is critically instrumental in allowing the active agent to be better targeted to the same receptor (folate receptor-alpha) found within the tubule of the kidney. Kipp focuses specifically on FC-rapa, but Knight teaches conjugating 4-hydroxy-tempol and proposes that the targeting technique may be applicable to other actives that are administered to the kidneys. This targeting technique is discussed as being useful for reducing the amount of a given active administered to treat a given kidney disease. In the case rapamycin, the targeting reduces the potential extrarenal effects of administering too high a dose, while the same technique allows a reduced contribution of superoxide (which is a cause of the disease being treated).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Response to Arguments
Applicants’ arguments with regard to the rejection of claims 1-6 and 8-20 under 35 USC 103(a) as being unpatentable over the combined teachings of Zhang et al., Kipp et al., and Knight et al. have been fully considered, but they are not persuasive.
Applicants traverse the rejection on the grounds that “combining Zhang’s nanoparticles with folate-conjugated rapamycin and folate-conjugated tempol will change the preferable size of Zhang’s nanoparticle in which case the nanoparticles would be useless, even for glomerular targeting.”
The Examiner, in response, respectfully submits that Applicants’ remarks concerning the combined teachings is not accompanied by any evidence that would support a teaching away (i.e., a clear showing in the art that would minimally suggest what such a particle size would be).
Applicants’ arguments, for the above reasons, are found unpersuasive. Said rejection is therefore maintained.
All claims under consideration remain rejected; no claims are allowed.
Conclusion
THIS ACTION IS MADE FINAL. Applicants are 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 extension fee 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Jeffrey T. Palenik whose telephone number is (571) 270-1966. The Examiner can normally be reached on 9:30 am - 7:00 pm; M-F (EST).
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Robert A. Wax can be reached on (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Jeffrey T. Palenik/
Primary Examiner, Art Unit 1615
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