DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Withdrawn Objections/Rejections
The objection to the drawings, under 37 CFR 1.83(a) because they fail to show color/grey scale distinction between the controls points and the treatment points on the graphs for Figures 9A, 9B, and 10A as described in the specification, is withdrawn. The substitute drawings filed overcome this objection.
The rejection of claims 268-269, 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is withdrawn. The amendments cancel claims 268-269, rendering the rejection moot.
The rejection of claim(s) 270-271, under 35 U.S.C. 102(a)(1) as being anticipated by Kishnani (Kishnani et al. NEUROLOGY 2007;68:99–109), is withdrawn. Claims 270-271 have been canceled rendering their rejection moot.
The following rejections of record are modified to take into consideration the amendments to the claims:
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 253-263, 268, and 269, as amended or previously presented, 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
Regarding claims 253-269, A method of clearing glycogen storage and improving cardiac, respiratory, and muscle function in a subject with Pompe disease comprising: administering to the subject an AAV2/8 vector comprising a transgene encoding GAA operably linked to MCK promoter, wherein the AAV vector is administered in an amount between 1x1013 vg/kg to 3 x1014 vg/kg and is administered (i) directly to muscle or heart or (ii) intravenously, and wherein said administering results in increased expression of GAA.
Regarding claims 270-271, these claims are enabled for the limitations above or an ERT therapy that administers rhGAA to said subject.
The specification does not reasonably provide enablement for:
1) treating or curing any and all symptoms of Pompe disease;
2) any AAV vector;
3) any route of administration; and
4) for claims 270-271, an agent that increases GAA expression.
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.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
Nature of Invention: Gene therapy for treating Pompe disease by administering an AAV vector encoding GAA.
Breadth of the Claims: The claims broadly recite, “a method of treating Pompe disease” without particular recitation of symptoms. As such the broadest reasonable interpretation (BRI) is any symptoms directly/primarily or indirect/secondarily caused by Pompe disease (i.e. a deficiency in GAA enzyme expression and/or activity). The claims also recite “administering” an AAV vector without any recitation of a route of administration. As such the BRI is any administration including systemically, intravenously, intrapulmonary, intramuscularly, intracranially, intrathecally, subdermal, subcutaneously, intraocular, intrarenal, peritoneal, topically, orally, among many other routes of administration. The claims do not specify any promoter used in the transgene. As such, the BRI of the promoter is any promoter capable of directing expression in any tissue. Regarding claims 270-271, the BRI of the claimed agent is any agent (protein, nucleic acid, DNA, RNA, iRNA, small molecule, conditional stimulation (electrical, mechanical, environments, etc…) among others. The agent can be one that directly impacts GAA (such as one that results in exogenous GAA protein or GAA gene expression) or indirectly (a factor that modulates upstream or downstream of GAA).
Specification Guidance:
Much of the specification’s disclosure describes different AAV viral dosage administration schedules. The specification describes the following (citations from pre-grant publication):
[0175] The present disclosure is based, in part, on the discovery of that particular doses of AAV vectors containing a GAA transgene are capable of achieving a therapeutic increase in GAA expression and activity in patients suffering from Pompe disease while suppressing toxic side effects. Particularly, doses of AAV vectors containing a transgene encoding GAA ranging from about 1×10.sup.13 vg/kg to about 3×10.sup.14 vg/kg (e.g., from about 3×10.sup.13 vg/kg to about 2×10.sup.14 vg/kg, such as a dose of about 4×10.sup.13 vg/kg, 5×10.sup.13 vg/kg, 6×10.sup.13 vg/kg, 7×10.sup.13 vg/kg, 8×10.sup.13 vg/kg, 9×10.sup.13 vg/kg, or 1×10.sup.14 vg/kg) can engender a beneficial increase in GAA expression and activity in a patient having Pompe disease while avoiding toxic side effects that can be associated with overexpression of GAA or administration of excessive quantities of viral vector. Using the compositions and methods of the disclosure, an AAV vector may be administered to the patient in an amount that is sufficient to enhance the patient's expression of GAA and reduce cellular accumulation of glycogen in the patient's neuronal and muscle tissue, without inducing toxic side effects.
[0178] Pompe disease (also known as glycogen storage disease type II, or GSD II) is caused by deficiency of the lysosomal enzyme GAA. The disease is an inborn error of metabolism in which a GAA deficiency ultimately results in glycogen accumulation in all tissues, especially striated muscle cells. In addition, the effect of glycogen accumulation within the central nervous system and its effect on skeletal muscle function have been documented.
[0179] Three clinical forms of this disorder are known: infantile, juvenile, and adult. Infantile Pompe disease has its onset shortly after birth and presents with progressive muscular weakness and cardiac failure. Infantile forms of Pompe are also characterized by a rapid development of cardiomyopathy, and patients often display myopathy and neuropathy leading to death typically in the first year of life. Symptoms in adult and juvenile patients occur later in life, and skeletal muscles and neurons are primarily involved. Patients exhibiting this form of Pompe disease eventually die due to respiratory insufficiency. Patients may exceptionally survive for more than six decades. There is a correlation between the severity of the disease and the residual acid α-glucosidase activity, the activity being 10-20% of normal in late onset and less than 2% in early onset forms of the disease.
[0184]-[0209] describe Dosing Regimens Involving AAV-GAA Vectors.
[0225] Viral vectors, such as AAV vectors and others described herein, containing the transcription regulatory element operably linked to a therapeutic transgene may be administered to a patient (e.g., a human patient) by a variety of routes of administration. The route of administration may vary, for example, with the onset and severity of disease, and may include, e.g., intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous, percutaneous, intratracheal, intraperitoneal, intraarterial, intravascular, inhalation, perfusion, lavage, and oral administration. Intravascular administration includes delivery into the vasculature of a patient. In some embodiments, the administration is into a vessel considered to be a vein (intravenous), and in some administration, the administration is into a vessel considered to be an artery (intraarterial). Veins include, but are not limited to, the internal jugular vein, a peripheral vein, a coronary vein, a hepatic vein, the portal vein, great saphenous vein, the pulmonary vein, superior vena cava, inferior vena cava, a gastric vein, a splenic vein, inferior mesenteric vein, superior mesenteric vein, cephalic vein, and/or femoral vein. Arteries include, but are not limited to, coronary artery, pulmonary artery, brachial artery, internal carotid artery, aortic arch, femoral artery, peripheral artery, and/or ciliary artery. It is contemplated that delivery may be through or to an arteriole or capillary.
Thus, the specification generically describes treating symptoms known in the art for Pompe disease and administering the vector by any route of administration known in the art. The vast majority of the specific guidance in the specification is to dosage and administration schedule with the described purpose of treating Pompe without eliciting harmful side effects of eliciting an immune response to the exogenous AAV vector and its payload and the exogenous transgene product.
Working Examples:
Example 1. Establishing Therapeutic Expression of Acid Alpha-Glucosidase in Mouse Models of Pompe Disease while Avoiding Toxic Side Effects.
[0230] The objective of this study was to evaluate the pharmacodynamic response together with potential toxicity of an AAV2/8 vector containing a GAA transgene operably linked to a muscle creatine kinase (MCK) promoter (referred to herein as “AAV2/8-MCK-GAA”) in adult Gaa.sup.−/− mice for a period of 12 weeks post dosing.
[0231] Seventy-two Gaa−/− mice and 18 wild type littermates were enrolled on study. Eighteen mice (9 each male and female; 10-12 weeks old) per group were administered either a single IV injection (via tail vein) of vehicle or AAV2/8-MCK-GAA (rAAV8-eMCK-hGAA) at doses of 0.3×10.sup.14, 1.0×10.sup.14, or 3.0×10.sup.14 vg/kg. Of these, Cohort-1 animals (5 males and 5 females per dose group plus vehicle controls) were designated for safety evaluation.
[0244] Analysis of diaphragm, heart, and quadricep biopsies revealed a dose-dependent decrease in glycogen concentration in AAV2/8-MCK-GAA-treated mice. Independently of which tissue was tested, the overall pattern of results across muscles was the same.
[0251] A positive effect of AAV2/8-MCK-GAA treatment was observed on glycogen clearance across all tested dosage groups and in all examined tissues. The greatest improvement was observed in the mid and high dose treatment groups, with glycogen normalized to the level observed in WT controls.
Example 2. Establishing Therapeutic Expression of Acid Alpha-Glucosidase in Mouse Models of Pompe Disease while Avoiding Toxic Side Effects
[0253] The objective of this GLP study was to examine the potential toxicity and safety pharmacology of AAV2/8-MCK-GAA in juvenile cynomolgus monkeys for a period of 12 weeks post-dosing.
[0254] Twenty-five juvenile monkeys 2-4 years old (14 males, 11 females) with low serum anti-AAV8 neutralizing antibody levels (titer of 5 or less for AAV2/8-MCK-GAA treated) were enrolled on study. Table 3 outlines the study design. Animals were administered a single IV infusion of vehicle, one of three doses (0.6×10.sup.14, 2×10.sup.14, or 5×10.sup.14 vg/kg) of AAV2/8-MCK-humanGAA (AAV2/8-MCK-GAA), or one dose (2×10.sup.14 vg/kg) of AAV2/8-MCK-cynomolgus GAA on study Day 1.
[0306] Administration of AAV2/8-MCK-GAA by intravenous infusion was tolerated up to 0.6×10.sup.14 vg/kg, but at the highest dose of 5×10.sup.14 vg/kg resulted in the unscheduled euthanasia of two animals, one female (animal 4501) on Day 79 and one male (animal 4003) on Day 82. Furthermore, in AAV2/8-MCK-cynomolgusGAA-treated animals, cynomolgus GAA-protein levels also increased in all tissues examined. Neither T-cell mediated anti-AAV8/GAA nor total anti-GAA antibodies appeared to negatively affect GAA protein or tissue enzyme activity levels.
[0308] In summary, the low dose (0.6×10.sup.14 vg/kg) of AAV2/8-MCK-GAA was well tolerated, whereas doses ≥2×10.sup.14 vg/kg were consistent with myocardial injury and accompanying mixed cell inflammation in muscles with occasional myofiber degeneration but also liver, adipose tissue, and dorsal root ganglia. An AAV2/8-MCK-GAA dose of 0.6×10.sup.14 vg/kg was defined as the no adverse effect limit (NOAEL).
No therapeutic or treatment of symptoms of Pompe were described in Example 2.
Example 3. Treatment of Pompe Disease in Human Patients by Administration of AAV-GAA Vectors in Accordance with a Dosing Regimen of the Disclosure. This example is a prophetic example describing how a human patient will be administered an AAV-GAA vector.
Thus, the working examples provides specific guidance to the use of one specific AAV vector comprising a transgene encoding GAA operably linked to a muscle specific MKC promoter that is administered at different doses (low, medium, and high) intravenously to a mouse model of Pompe disease or a monkey without Pompe disease both in a single dose. The examples narrowly describe that mouse model demonstrated improved glycogen storage clearance from the muscle and heart. The monkey experiment demonstrated a dosage limit for tolerance of the AAV vector that allowed for increased GAA expression in muscle and heart that did not result in anti-AAV and anti-GAA expression at a level that altered GAA protein increase.
However, the specification fails to provide broader specific guidance to any other route of administration, any other vectors that have promoters that express in tissue other than muscle, any other AAV vector than AAV2/8 and treatment any and all symptoms of Pompe disease. As such, the specification does not enable these broader embodiments.
Regarding claims 270-271, while the specification recites these claims, the specification does not provide specific guidance to any other agent than AAV-GAA gene therapy vectors. As such, the specification and working examples of the disclosure fails to provide enabling guidance to any other “agent” as claimed.
State of the Art:
Traverna et al (Aging 12(15):15856-15874, 2020) reports, “ERT [GAA protein therapy] improves the cardiac and respiratory functions and contributes to extend the lifespan of IOPD patients. However, it is frequently associated with the development of neutralizing humoral immune responses against rhGAA that decreases treatment efficacy and survival…. The limitations of therapy have encouraged efforts to enhance the efficacy of the current therapy and to develop new approaches including gene therapy… The results showed an efficient clearance of glycogen storage in muscle and the improvement of the muscle and the cardiac and respiratory functions. One limitation of the systemic route to target muscles is the use of high doses of vector…. Moreover, muscle specific expression of GAA can increase the risk to develop anti-GAA antibodies causing a possible immunotoxicity. Another strategy to develop gene therapy for PD consists in the stable expression of GAA in liver. It was demonstrated that adenoviral GAA transfer mediates the crosscorrection in skeletal muscles. The major limitation of this approach for PD is that hepatic gene transfer does not persist at long term.” See page 15865. Also see Ronzitti et al (Ann Transl Med 2019;7(13):287 dx.doi.org/10.21037/atm.pp 1-15).
Regarding claims 270-271, ERT is the only other therapy described around the time of filing that has some but limited ability to treat some symptoms of Pompe disease. However, as discussed above, the prior art teaches a great deal of unpredictability in ERT, GAA gene therapy, and overall treatment of Pompe disease. As such, the art does not provide adequate specific guidance to “an agent that increases GAA expression” other then ERT and GAA gene therapy to some degree. Thus, the art does not provide enabling guidance to the breadth of the claimed agent to supplement the shortcomings of the specification.
Thus the state of the art before the time of filing and post-filing describes a high degree of unpredictability in both ERT and GAA gene therapy approaches. While the specification does not provide some guidance to administrations schedules that may mediate some of the unpredictabilites AAV vector and GAA elicited immune responses, it fails to provide specific guidance to overcome issue of using any route of administration, any vector, expression of the GAA in any tissue, and treating any symptom of Pompe disease as the claims embrace. Furthermore, the specification appears to overcome some of the issues of immune response to the AAV vector and GAA via the use of one specific vector that has muscles specific expression and it delivered in one specific way at a specific concentration. As such, these element appears to be required for the improvement. Thus, the breadth of the claims lack enablement because the specification solely provides specific guidance to a much narrow gene therapy approach using one specific AAV vector encoding GAA operably liked to a MCK promoter administered intravenously that improves glycogen storage clearance and is expressed in a manner that increases GAA without interference with anti-AAV and anti-GAA immune response. Given the great degree of unpredictability in this art, a great deal of discovery experimentation would be required post-filing to determine its potential as a means of treat Pompe disease as broadly claimed. This level of post-filing experiment would be considered beyond routine optimization and thus would be undue.
Response to Arguments
Applicant's arguments filed 10/9/2025 have been fully considered but they are not persuasive.
Applicant traverses this rejection on the grounds that the presently claimed method meets the standard of “treatment” as set forth by the definition of this term provided in the specification. Applicant refers to page 41, lines 5-21 of the specification, Example 1, and figures 1B and 2A of the prior art presented in the 103 rejection of record in the previous office action.
In response, Page 41, lines 5-6 recite the following, “the terms ‘treat’ or ‘treatment’ refers to therapeutic treatment, in which the object is to prevent or slow down (lessen) an undesired disorder”. This definition is generic in nature. Lines 6-7 states, “such as the progression of a lysosomal storage disorder, such as Pompe disease”. These recitations and the descriptions that follow in the remainder of the paragraph are not part of the definition, rather examples and embodiments. So the breadth of treatment by definition provided in the specification is prevent, slow down, lessen an undesired disorder. In the instant of claimed method the undesired disorder is Pomp2 disease in a human patient. As such, the interpretation of treatment by Examiner in the rejection is in line with the definition provided in the specification. However, while the specification generically contemplates preventing, slowing down, lessening Pompe disease in any way. The specification solely provide specific guidance to a small number of species, particularly clearing glycogen storage and improving cardiac, respiratory, and muscle function. The specification and working examples in no way provide any evidence of any type of prevention of Pomp disease, any type of slowing down of the disease and only a small number of symptoms of Pompe disease that are lessened. Applicant refers to Example 1 and the disclosures of Bryon used in the 103 rejection as evidence. However, Example 1 and the Byron more narrowly describe clearing glycogen storage and improving cardiac, respiratory, and muscle function as the rejection acknowledges are enabled. Further, as stated in the State of the Art section of the scope of enablement rejection, treating Pompe disease is unpredictable. Applicant has not provided address these teaches provided in the art. Applicant also has not provided further evidence that more symptoms of Pompe disease can predictably be treated by the claimed method but only the symptoms the rejection has identified as enabled. As such, absent evidence to the contrary, the great breadth of “treating Pompe disease” as claimed in not enabled.
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.
Claim(s) 253-256, as amended or previously presented, is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023).
Regarding claim 253, Bryne discloses administering an AAV virion to a subject having GAA deficiency (i.e. Pompe disease), resulting in respiratory deficit and improving phrenic nerve activity (p. 10, last paragraph to p. 11, line 7). Expected dosage for IV administration will be in the range of 1012-1015 . For example for a 70 kg human, a 1 to 10 ml injection (i.e. single dose) of 1012-1015 particles is an appropriate does (p. 25, lines 10-15). Bryan discloses the AAV can be an rAAV2 vector encoding GAA pseudotyped with a capsid gene derived from AAV of a different serotype (e.g., AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9), an example AAV2/9 (p. 22, lines 15-25). These disclosure encompass both AAV2/8 and AAV2/9. Bryan discloses a MKC promoter (p. 17, lines 18-22).
Regarding claims 254-255, the above dosage range comprises the dosage of the claimed ranges.
Regarding claim 256, a single 1 to 10 ml injection as discussed above discloses a single dose as claimed.
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.
(1) Claim(s) 268 is/are rejected under 35 U.S.C. 103 as being unpatentable over Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023) as applied to claims 253-256, 264-267, and 270-272 above, and further in view of Xiao (US 7,001,761 pub date:2/16/2006).
Regarding claim 268, Bryne teaches the claim limitations as discussed above. Bryne does not teach that the MCK promoter is specifically a species having at least 85% identical to SEQ ID NO:1.
However, at the time of the invention, Xiao teaches multiple AAV vectors comprising mini-dystrophin genes operable linked to a MCK promoter (SEQ ID NOS:26-32). The promoters of SEQ ID NOS:26-30 and 32, taught by Xiao are 100% identical to SEQ ID NO:1 of the instant application. The promoter of SEQ ID NO:31, taught by Xiao, is 97.9% identical to SEQ ID NO:1 of the instant application (col 13, lines 1-31). Further Xiao teaches that the MCK promoter of these AAV vectors successfully induced muscle specific expression of the mini-gene which lead to the therapeutic result of improve muscle contractile force (col 17; lines 22-27). Thus Xiao at least demonstrates that the MCK promoters taught by Xiao are a predictable equivalent to the MCK promoter of SEQ ID NO:1 in the instant application. Further, one would be motivated to use the promoters of SEQ ID NOS:26-32 taught by Xiao because Xiao teaches that the promoter drives muscle specific expression of a transgene at therapeutic levels.
As such, it would have been obvious to an artisan of ordinary skill before the time of effectively filing, to simply substitute the MCK promoter of SEQ ID NOS:26-32, taught by Xiao, in place of the MCK promoter used in Bryne to predictably arrive at the AAV vector and method of claim 268. One would have a reasonable expectation of success with the substitution because the methods of such a substitution were well known in the art and because Xiao provide multiple examples of successfully using the MCK promoter in AAV vectors for muscle specific expression. Further, one would be motivated to use the MCK promoter of Xiao in the method of Bryne because Xiao demonstrates that it is a strong promoter for muscle-specific expression at therapeutic levels. Thus, Bryne in view of Xiao renders claim 268 obvious.
(2) Claim(s) 269 is/are rejected under 35 U.S.C. 103 as being unpatentable over Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023) as applied to claims 253-256, 264-267, and 270-272 above, and further in view of Medin (US 11,597,917 effectively filed 6/6/2017).
Regarding claim 269, Bryne teaches the claim limitations as discussed above. Bryne does not teach that the GAA has an amino acid sequence that is at least 85% identical to SEQ ID NO:2.
However, Medin teaches a viral vector comprising a gene encoding a GAA amino acid sequence set forth in SEQ ID NO:9. SEQ ID NO:9 is an mRNA sequence encoding an amino acid sequence with 100% identity to SEQ ID NO:2 of the instant claim. This viral vector is intended for treatment of Pompe disease (col 10, last paragraph to col 11, line 8).
As such, it would have been obvious to an artisan of ordinary skill before the time of effectively filing to simply substitute the GAA transgene sequence of Bryne with SEQ ID NO:9, taught by Medin to predictably arrive at the method of claim 269. One would have a reasonable expectation of success because molecular biology methods for making the substitution were long established and predicable in the prior art and Medin teaches that SEQ ID NO:9 can be used in viral vectors and can be use to treat Pompe disease and therefore is a predicable equivalent sequence serving the same purpose as taught by Bryne. As such, Bryne in view of Medin render claim 269 obvious.
(3) Claim(s) 258-263 is/are rejected under 35 U.S.C. 103 as being unpatentable over Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023).
Regarding claims 258-263, Bryne teaches the limitations of the claimed method including the viral dosage as taught above. Bryne is silent on the delivery of a dose 2 or more times, the total dosage over multiple AAV administrations, and the timing of delivery of multiple dosages as recited in these claims.
However, Bryne teaches that toxicity and therapeutic efficacy of AAV administration in the methods of their invention can be determined by standard pharmaceutical procedures. Further Bryne teaches as is well known in the medical and veterinary arts, dosage for any one animal depends on many factors, including subject’s size, body surface area, age the particular composition administered, time, route of administration, general health, and other drugs administered concurrently (p. 25, lines 1-15). As such, Bryne teaches that determining the amount, number of dosages, and timing of dosages is routine in the prior art. Therefore, it would have been obvious to an artisan of ordinary skill before the time of effectively filing to determine the optimal dosage, number of administrations, and timing of the number of administration using well established pharmacological methods to predictably arrive at the limitations of the claims.
Further, However, MPEP § 2144.05 (II) states the following:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Dosage administration schedule is ultimately a determination of concentration ranges A review of the specification in the instant application fails to provide evidence that the claimed dosage administration schedule are critical. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effectively filing Smith to try a finite number of possible concentration of the AAV vector through routine optimization. An artisan would have a reasonable expectation of success in optimizing the concentrations because determine method of determining dosage administration schedules (i.e. effective concentration) were long established in the art as demonstrated by Bryne. Thus Bryne renders the instant claims obvious.
Response to Arguments
Applicant's arguments filed 10/9/2025 have been fully considered but they are not persuasive.
Regarding Bryne, Applicant submits Bryne neither prophetically nor experimentally test an AAV2/8 comprising an MCK promoter coupled to GAA transgene. Bryne specifically exemplifies AAV vectors having distinct serotypes and regulatory elements that drive AAV. Bryne evaluates an AAV2/9 vector comprising a GAA transgene operably linked to CMV or DES promoter.
In response, disclosure by a prior art is not limited to it narrowests disclosures or examples reduced to practice. Bryne does reduce to practice a vector that is structurally different from the claimed vector. However, this does not negate that Bryne also broadly discloses the AAV2/8 vector, the use of a MCK promoter operably linked to GAA transgene delivered intravenously to a patient in the range of the claimed dosage.
Applicant submits Bryne does not provide motivation to choose an all together different promoter than the CMV or DES promoters. In response, Bryne expressly contemplates using the MCK promoter. As such, Byne clear intends embodiments that comprise the MCK promoter.
Applicant submits that Bryne does not even select the MCK promoter for empirical testing and asserts that Bryne teaches away from MCK promoter and towards other promoters. Applicant refers to the art of Pacak stating that the CMV promoter followed by the DES and alpha-MHC promoter were found to be the most effective in driving AAV transgene expression in tissues impacted by Pompe disease. As such, Bryne and Pacak would have motivated one of skill in the art to pursue a different capsid and promoter.
In response, Applicant is reading limitations into Bryne and Pacak that are not present. Bryne expressly contemplates embodiments that use a MCK promoter as discussed above. Bryne is not limited to only it disclosures of its reduction to practice and Bryne provide not express or implicit suggestion that one should not use the MCK promoter. In contrast, the MCK promoter is contemplated as a possible promoter for use in their invention as is the AAV2/8 serotype. As such, Bryne does not teach away from the claimed vector serotype and promoter. Pacak does not provide a teaching away but merely recites the optimal results found in their experimental studies. Pacak does not expressly or implicitly suggest that the MCK promoter does not function. Further, a teaching of one design being better than another, as Applicant suggest Pacak does, does not negate that Bryne discloses the claimed AAV2/8 vector and MCK promoter embodiments and that this embodiment would not function. As such, Pacak also does not provide evidence of teaching away.
Applicant suggest that the combined features of the claimed method effectuates surprising and advantageous results. The claimed method achieved substantially higher GAA activity than Bryne. The claimed method also show an almost 100% reduction in accumulated glycogen in the heart and restoration of glycogen to levels comparable to vehicle treated wild type controls. As such, Bryne as used in the 102 and 103 do not render the claims obvious.
In response, Applicant is reading limitations into the claims not required by them. The claims do not recite any level of GAA activity or reducing in glycogen accumulation in the heart. As such, the claims do not require any of the improvements cited by Applicant and only generically require “treating Pompe disease”. Bryne discloses treatment of Pompe and the claimed AAV vector. As such, the limitations of the claimed are met by Bryne. Thus the limitations of the claims have been disclosed as described in the 102 rejection and taught as described in the 103 rejection.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632