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 .
Restriction/Election
Applicant’s election without traverse of Group I, claims 1-14, in the reply filed on 11/20/25 is acknowledged.
Claims 15-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/20/25.
Claims Rejections 35 USC 112(A)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2 and 7-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating or delaying the onset of Type I diabetes does not reasonably provide enablement for preventing diabetes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (reversing the PTO's determination that claims directed to methods for detection of hepatitis B surface antigens did not satisfy the enablement requirement). In Wands, the court noted that there was no disagreement as to the facts, but merely a disagreement as to the interpretation of the data and the conclusion to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The Court held that the specification was enabling with respect to the claims at issue and found that "there was considerable direction and guidance" in the specification; there was "a high level of skill in the art at the time the application was filed;" and "all of the methods needed to practice the invention were well known." 858 F.2d at 740, 8 USPQ2d at 1406. After considering all the factors related to the enablement issue, the court concluded that "it would not require undue experimentation to obtain antibodies needed to practice the claimed invention." Id., 8 USPQ2d at 1407.
(1) The nature of the invention and (5) The breadth of the claims:
The invention is drawn to a method of preventing and treating Type 1 diabetes, but the nature of T1D does not support claims to prevention, as the state of the art recognizes that many trials have failed to prevent diabetes, as will be discussed below. The claims are drawn to treating, preventing, delaying the onset of T1D as a subset of prevention. However, the present application does not contain definitive evidence that diabetes can be prevented by the administration of the claimed PC-Lyso-PS liposome comprising insulin.
(2) The state of the prior art:
In regards to “preventing diabetes,” it is well known in the art that Type 1 diabetes cannot be prevented (Beik et al. Prevention of Type 1 Diabetes: Past Experiences and Future Opportunities, 2020, J. Clin. Med. 2020, 9, 2805). T1D is a complex autoimmune disease, characterized by immune-mediated destruction of pancreatic β-islet cells, which generally occurs years before clinical diagnosis (Beik et al., See Abstract, p. 1-2). The strongest predictor known for T1D is genetic susceptibility associated with HLA class II alleles, but these are only considered one of many risk factors for T1D, not definitive factors (Jacobsen et al. Frontiers in Endocrinology, 2018, Vol. 9, No. 70; p. 2, Col. 1-2).
Prevention trials have consistently failed to show that one single genetic or environmental factor is responsible for T1D onset. There have been many large sample, globally supported trails for various methods of prevention, including antigen-based therapy, immunomodulatory, and immunosuppression therapies and primary dietary prevention, among others (Jacobsen et al., Table 1, Beik et al. Tables 2-3). As such, it is well known that Type I diabetes is not preventable, as it a complex multifactorial disease, caused by genetic and other factors, which are not currently known in the art.
(3) The relative skill of those in the art:
The relative skill of those in the art is high.
(4) The predictability or unpredictability of the art:
Applicant’s claims are based on predicting subjects that would be susceptible to diabetes and determining the patient population that is susceptible to T1D in all cases. The claims do not identify the patient population by way of any risk factors or conditions, thus implying that the anyone can be prevented from the onset of T1D. However, the examples of the specification have not shown who will be susceptible diabetes or that in can be prevented in any subjects. There are too many variables for predictable experimentation, and many past trial have failed to prevent T1D, making the predictability of preventing T1D low.
(6) The amount of direction or guidance presented and (7) The presence or absence of working examples:
Applicant’s specification concludes that Type 1 diabetes can be prevented because the results of one experiment showed diabetes in NOD/ShiLtJ, (a standard model for T1D already having insulitis), were shown to have delayed the onset of T1D, lowered antibody titers that are correlated with T1D and lowered CD8+T cells (example 1).
However, as discussed above, the state of the art recognizes that diabetes has a widely variable patient class, as those susceptible to diabetes are subject to a variety of factor which cause different types of diabetes. (Beik et al., abstract, Jacobsen et al., abstract, p. 1-2).
The specification has not provided clear guidance as to how to determine the patient population, since diabetes is an insulin dependent disease with a variety of unknown causes and patient predispositions, which requires further guidance as to the patient population that should be receiving the claimed insulin liposomes. Furthermore, even if the compound were administered to a test group of individuals, it is not known how much of the compound is needed for prevention, what type of insulin regimen is needed for prevention, and whether or not the lowering of blood glucose in general by the compound would prevent diabetes in all cases.
(8) The quantity of experimentation necessary:
Because it is uncertain to predict the patient population susceptible for diabetes as well as at what time in life it will onset and to what population the compound should be administered, one of ordinary skill in the art would be burdened with undue “painstaking experimentation study” to determine how to use the claimed compound to prevent diabetes.
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.
Claim(s) 1, 3-10 and 12-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Blankert et al. (US2017/0209371A1) in view of Kim et al. (Mol Pharm. 2018 October 01; 15(10): 4756–4763).
Blankert teaches compositions and methods for inducing immune tolerance to proteins by administering proteins complexed with liposomes comprising PS and PC, wherein at least part of the PS is present as lyso-PS abstract). Blankert further teaches liposomes which comprise phosphatidylcholine (PC) and lysophosphatidylserine (lyso-PS), wherein the molar ratio of PC to lyso-PS is from 90:10 to 60:40. The acyl chain of the lyso-PS can contain from 14 to 22 carbons [0006]. This reference further teaches that a length of 18 with one double bond (18:1, oleic acid) was particularly effective in induction of immune tolerance, and that the acyl chain length of the PC chains can be from 12-22 [0006]. This reference further teaches that unwanted immune response against self-proteins leads to autoimmune conditions such as diabetes [0003].
Specifically, Blankert teaches compositions comprising a plurality of liposomes, wherein the liposomes comprise phosphatidylcholine (PC) and lysophosphatidylserine (lyso-PS), wherein the ratio of PC to lyso-PS is from 90:10 to 60:40 or from 85:15 to 70:30, and the acyl chain of the lyso-PS can be oleic acid (18:1) [0072]. Blankert further teaches that PC may be present as dimyristoyl-sn-glycero-3 phosphatidylcholine (DMPC) [0072]. This reference also teaches that the size of the liposomes is from 80 to 150 nm (90% of the population) and the zeta potential of the liposomes is from −10 to −15 [0072]. Blankert also teaches that the liposomes may be complexed to an antigenic polypeptide, such as insulin and the PC and lyso-PS may be the only phospholipids present in the bilayer of the liposome [0072]. This reference further teaches that the protein for delivery may be the protein may be partly or fully intercalated in the bilayer [0044]. This reference further teaches a method of making the liposomes by associating proteins with the liposomes by incubation at 37° C and the returned to room temperature [0084-0085]. Additionally, this reference teaches that the or the formation of these liposomes, the protein to lipid ratio used was 1:10,000 [0084].
The difference between the prior art and the instant claims is that the prior art does not reduce to practice administering the insulin carrying liposome to a subject.
Kim teaches that since its discovery in 1922, porcine insulin, human recombinant insulin, modified/engineered insulin and their pharmaceutical formulations have saved the lives of type 1 diabetes mellitus (T1DM) patients by subcutaneous (SC) injections multiple times a day (abstract). This reference further teaches that administering insulin liposomes through oral insulin delivery in vivo was done with various doses of insulin-loaded partially uncapped liposomes (p. 10, para. 1; abstract; Figure 5a). The blood glucose level showed that it was dose-dependent on the dosing regimen and the results showed that T1D was treatable with insulin nanoparticles (p. 10, para. 1-2).
It would have been obvious to one of ordinary skill in the art at the filing date of the invention to have taken the insulin loaded liposomes of Blankert and used them to treat T1D because Kim teaches that oral insulin liposome were effective in treating T1D in vivo. One would be motivated to do so because both references teach insulin liposomes and Kim teaches that insulin liposomes are effective in treating T1D by regulating blood glucose levels. As such, there is a reasonable expectation of success that the insulin liposomes of Blankert will be effective in the T1D treatment method of Kim.
This meets the limitations of claim 1 because Blankert teaches the same PC to lyso-PC liposomes in the same ratios with insulin as a loadable drug, and Kim teaches that insulin liposome effectively treat T1D. Claim 3 is met because blood glucose level were normalized, which is suppressing a symptom of T1D. Claims 4 and 5 are met because Kim teaches that insulin regulates blood glucose levels. Claims 7-9 are met because Blankert teaches an acyl chain oleic acid, a ratio of 85:15 to 70:30 and DMPC as the PC component of the liposome. Claim 10 is met because Blankert teaches liposome without other phospholipids in the bilayer. Claim 12 is met because both Blankert and Kim teach oral administration of insulin liposomes. Claim 13 is met because Blankert teaches contacting the proteins to be loaded at 35⁰C, which is “up to” 70⁰C, and then returning them to room temperature. Claim 14 is met because Blankert teaches a ratio of 1:10,000.
Claim(s) 1-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Blankert et al. (US2017/0209371A1) in view of Kim et al. (Mol Pharm. 2018 October 01; 15(10): 4756–4763), as applied to claims 1, 3-10 and 12-14 above, and in further view of Bonifacio et al. (JAMA. 2015;313(15):1541-1549).
The difference between the prior art and the instant claims is that the prior art does not teach delaying the onset of diabetes or administering the compound to subject having prediabetes.
Bonifacio teaches that oral administration of insulin reduces the development of diabetes in an animal model, and that the protective mechanism is thought to involve the induction of insulin-specific regulatory T cells (p. 1542, Col. 1). This reference further teaches that antigen-specific therapy with insulin before the development of autoantibodies may induce protective immune responses to prevent or delay the emergence of autoimmunity and type 1 diabetes in genetically at-risk children (1542, Col. 1).
It would have been obvious to one of ordinary skill in the art at the filing date of the invention to have taken the insulin liposomes of Blankert and used them in the oral delivery method of delaying the onset of diabetes in subjects at risk for diabetes. One would be motivated to do so because Bonifacio teaches that administration of antigen-specific therapy with insulin before the development of autoantibodies may induce protective immune responses to delay the emergence of autoimmunity and type 1 diabetes. As such, there is a reasonable expectation of success, that insulin can be administered to at risk and prediabetic individuals to delay the onset of type 1 diabetes.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANETTE M LIEB whose telephone number is (571)270-3490. The examiner can normally be reached M-F 10-7.
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654