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 .
Remarks
The amendments and remarks filed on 02/19/2026 have been entered and considered. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior office action. The rejections and/or objections presented herein are the only rejections and/or objections currently outstanding. Any previously presented objections or rejections that are not presented in this Office Action are withdrawn. Claims 19, 22, 26-27, 30-31, 32-36, and 39 are pending; Claims 1-18, 20-21, 23-25, 28-29, 32-34, and 37-38 are cancelled; Claim 19 is amended; and Claims 19, 22, 26-27, 30-31, 32-36, and 39 are under examination.
Withdrawal of Rejections
The rejection of claim 23 under 35 U.S.C. 112(b) is withdrawn due to the cancellation of the claim.
Claim Rejections - 35 USC § 103
Claims 19, 22, 26-27, 30-31, 35-36, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Okuyama et al. (WO 2017/116066, published on July 6, 2017, cited in IDS), as evidenced by Thorne et al. (US 2017/0105927, Apr. 20, 2017, of record). This rejection is maintained.
Okuyama et al. teach a method of treating Hunter Syndrome, comprising: a step of administering intracerebroventricularly (ICV) to a subject in need of treatment a therapeutically effective dose of an ICV formulation comprising Idursulfase-beta (IDS-β) at a concentration ranging from ~ 0.1 mg/ml to ~ 60 mg/ml or specifically a concentration of 15 mg/ml (Note: this reads on the concentration “15 mg/ml” in claim 19), Sodium chloride at a concentration of ~ 150 mM, polysorbate 20 at a concentration of ~ 0.05 mg/ml, and a pH of approximately 6 (Note: these teachings respectively read on the “pH”, “polysorbate”, “sodium chloride”, and their concentrations in claims 19, 35, and/or 36); wherein the ICV administration is performed once every month or once every four weeks (Note: these teachings meet the limitation “an interval of 4 weeks” recited in the claim 19), and an effective dose of IDS-β is from approximately 1 mg to approximately 30 mg; wherein the ICV administration is performed by direct administration of IDS-β into cerebral ventricles or a lateral ventricle without inducing adverse effects (abstract, Claims 1, 3, and 6, para 0013/lines 1-6 and 9-10, para 87/lines 5-6, para 109/lines 5-6). Regarding the limitation SEQ ID NO:1 recited in the claim 19, Okuyama et al. further teach the IDS-β comprises a protein having an amino acid sequence of SEQ ID NO:1 (para 0049/lines 2-3, page 18), which has 100% identity to the sequence of instantly claimed SEQ ID NO:1 (see the sequence in page 18 of Okuyama). Thus, Idursulfase-beta (IDS-β) taught by Okuyama et al. meets the claimed limitation about SEQ ID NO. 1. Regarding the steps 1) -4) for the administration in claim 19, Okuyama et al. further teach that the JCV administration in their method can be conducted through an intraventricular catheter system comprising a reservoir and a catheter connected to the reservoir (Claims 8), and their method further comprises steps: surgically implanting the intraventricular catheter system, wherein the reservoir is placed between the scalp and the brain of the subject in need of treatment and the end of the catheter is placed inside the ventricle of the subject such that the inner space of the reservoir is connected to the inner space of the ventricle through the inner space of the catheter so that cerebrospinal fluid flows from the ventricle into said reservoir to fill the reservoir; drawing out 0.1-5 ml of cerebrospinal fluid from the reservoir at a flow rate of 0.1-60 ml/minute; injecting 0.1-5 ml of the ICV formulation into the reservoir at a flow rate of 0.1-60 ml/minute; and allowing the ICV formulation to flow from the reservoir through the catheter into the ventricle (Claim 8). Thus, the administration steps of Okuyama et al. meet the requirement of steps 1) -4) of the administration recited in the claim 19.
Regarding the frequency “at least 6 times” of the administration recited in Claim 19, Okuyama et al. teach the JCV administration monthly dosing is performed for more than six months, a year, or more (page 11, lines 3-4), i.e. the administration can be performed for more than 6 times, 12 times, or more times. Thus, the administration frequency taught by Okuyama et al. meet the requirement of at least 6 times recited in the claim 19. Regarding the claimed IDS-β dose “30 mg” recited in Claim 19, the dose range of about 1 mg to about 30 mg taught by Okuyama et al. encompasses the claimed 30 mg, thus rendering the claimed dose “30 mg” to be obvious. See MPEP 2144.05.
Regarding the limitation about the clinical outcome of not causing the severe adverse effect in Claim 19, Okuyama et al. teach that the administration is highly efficient, clinically desirable, and patient-friendly and it does not cause adverse effects such as severe adaptive immune response (paras 0013/last 6 lines), which encompasses severe T-cell mediated adaptive immune response, toxicity and death of the subject. Regarding the limitation about the clinical outcome of improving brain function or learning-memory ability in the claim 19, Okuyama et al. teach that there is correlation between HS-derived disaccharides and mental retardation in patients (para 11, line 2-5). Given administration of IDS-β in the method of Okuyama et al. reduces HS accumulation in the brain, it is expected that administration results in decreased HS-derived disaccharides, thus leading to reduced mental retardation and improved metal function. Furthermore, Okuyama et al. teach that administration of IDS-β reduces severity of symptoms of the Hunter syndrome, such as cognitive impairment (para 0066, lines 1-4), i.e. improves brain function and learning-memory ability, thus meeting the requirement of the limitation. Regarding the limitation about the clinical outcome of decreasing HS accumulation and cellular vacuolization in Claim 19, Okuyama et al. expressively teach that the administration of IDS-β to the patient decreases HS accumulation in the brain and cerebrospinal fluid, and decreases cellular vacuolization in brain cells (paras 0034 and 0064/lines 2-4 from bottom). Okuyama et al. are silent about a decrease in HS accumulation at a level 20% or more. However, the clinical outcome limitations in the claim 19 are directed to what the claimed method (administration treatment) does to the subject, not to what the method is (i.e. not to steps of the claimed method). Okuyama et al. suggest a method comprising all step limitations recited in the instant claims. It is presumed that methods having substantially the same steps are capable of generating substantially the same clinical outcomes.
Thus, the teachings of Okuyama et al. meet the claimed limitations in the claim 19.
Regarding Claim 22, Okuyama et al. teach the IDS-β is administered to the right lateral ventricle (para 87/line 6).
Regarding Claim 26, Okuyama et al. teach the subject in their method can be a human/child (paras 10/line 5, 109/line 10).
Regarding Claim 27, Okuyama et al. teach the subject is a mouse (paras 105, 106, and 109). The claimed method of treating a mouse would be obvious over the teachings of Okuyama et al. in view of the fact that the treatment conditions including IDS-β dosages taught by the cited prior art can be readily modified through routine optimization for treating a mouse subject. See MPEP 2144.05, which summarily states that inventions that mainly depend on the dosages and/or overlapping ranges are rendered obvious. Therefore, the claimed method cannot be considered as being novel just for adjusting dosages of a known drug for treatment.
Regarding Claims 30-31, Okuyama et al. teach that their method further comprises applying at least one additional form of enzyme replacement therapy to the subject for treatment of Hunter Syndrome, wherein the additional form of enzyme replacement therapy is selected from a group consisting of intravenous administration and subcutaneous administration (Claims 9 and 10, paras 23-24).
Regarding Claim 39, it is noted that the brain has only four ventricles, which include two lateral ventricles (“LV”), one right lateral ventricle and one left lateral ventricle on each side of the brain); a third ventricle (“3V”); and a fourth ventricle (“4V”), as evidenced by Thorne et al. (see para 0006/lines 1-7, Fig. 1C and 1D). It is an obvious design choice to administer IDS-β to a single lateral ventricle (a left or right ventricle) or to both lateral ventricles (both left and right ventricles) in the method of Okuyama et al, because both ways can directly deliver the IDS-β to the cerebrospinal fluid (CSF) in ventricles so as to treat Hunter syndromes. Given Okuyama et al. teach the IDS-β is directly introduced either to a lateral ventricle or to more than one ventricle, The claimed limitation about directly introducing the IDS-β composition to both of right lateral ventricle and left lateral ventricle of the subject would have been obvious.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 19, 22, 26-27, 30-31, 35-36, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (US 2014/0271598, 2014, of record) in view of Keimei et al. (US 2005/0208090, 2005, of record), Thorne et al. (US 2017/0105927, published on Apr. 20, 2017, of record) and Lad et al. (US 20100305492, 2010, of record).
Zhu et al. teach a method for treating a subject with a lysosomal storage disease, specifically Hunter Syndrome, comprising a step of intrathecal administration of a stable formulation/composition comprising iduronate-2-sulfatase (I2S) as a lysosomal enzyme, NaCl salt, and polysorbate 20, for direct CNS delivery of the enzyme to cerebrospinal fluids (CNF) of the subject (abstract, claims 1, 23, and 32-33, paras 0011-12), wherein the iduronate-2-sulfatase/I2S has a concentration of 1-300, 1-50 mg/ml, or specifically 15 mg/ml (para 0014/lines 5-7 and 10) (Note: these concentrations either encompass or read on the claimed concentration “15 mg/ml” in Claim 19); wherein the composition has a pH of 5.5-6.5, specifically, about 6.0, and the composition comprises: the NaCl at a concentration in a range of about 137-154 mM, specifically about 154 mM, and the polysorbate 20 at a concentration of up to 0.02%, specifically, about 0.005% (Claim 23, paras 015/last 4 lines, 0016/last 4 lines, and 0017/last 3 lines) (Note: these teachings respectively read on the “pH”, “polysorbate”, “sodium chloride”, and the concentration of NaCl in claims 19, 35, and/or 36); wherein the administration is performed at an interval, which depends on the nature, severity and extent of the disease and can be once every month (i.e. monthly) for a time period such as up to a year (paras 0030/line 3, and 0261/lines 4-7 and 13-14, page 23/para 0262/lines 4-9 from bottom), specifically, once every month for a total of 6 months (Example 9/ para 0405/lines 4-5) (i.e. the administering is performed for a total of 6 times, which reads on the claimed limitation “at least 6 times” in claim 19); wherein the subject is any mammal such as human (para 0122); wherein the composition is a pharmaceutical composition (paras 0122/lines 4-5, 0131/last 3 lines); wherein the intrathecal administration is used in conjunction with intravenous administration or with subcutaneous administration (page 3/right col/paras 0030-32, paras 0262/lines 1-3) (Note: the intravenous and subcutaneous administration meet the additional enzyme replacement therapy recited in in claims 30-31); and wherein the composition is delivered with a catheter system comprising a catheter and reservoir, to which the catheter is connected (para 0202, lines 3 from bottom). Regarding the limitation “iduronate-2-sulfatase beta (IDS-β)” comprising the sequence of “SEQ ID NO:1” recited in the claim 19, Zhu et al. teach the I2S (iduronate-2-sulfatase) comprises an amino acid sequence of SEQ ID NO:1 (para 0015/lines 3-4), and the amino acid sequence of SEQ ID NO:1 listed in pages 38-40 has 100% identity to the sequence of instantly claimed SEQ ID NO:1. As such, the I2S (iduronate-2-sulfatase) comprising the sequence of SEQ ID NO:1, taught by Zhu et al., meeting the claimed limitation about IDS-β and SEQ ID NO:1.
Regarding the limitation about administering the composition “at an interval of 4 weeks” recited in Claim 19, Zhu et al. teach administering monthly or every month, i.e. at an interval of one month. Given that one month has about 4 weeks, the claimed interval of 4 weeks is reasonably suggested by the interval of one month taught by Zhu et al. See MPEP 2144.05(I), which states “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”. Thus, the claimed interval would be obvious over the teachings of Zhou et al.
Regarding the dose “30 mg” recited in Claim 19, Examiner notes that a dose for the administration is readily adjustable and optimized based on specific conditions such as severity and extent of the disease and frequency of delivery. Zhu et al. further teach a therapeutic effective dose that is in a range such as from about 0.005 to about 60 , from about 0.005 to about 50, and from about 0.005 to about 40 mg/kg brain weight (para 0266/lines 11-14). Based on exampled brain weight, 1.30 kg, for boys of 4-5 years old listed in Table 5, these ranges can be converted to a therapeutic effective dose range of up to 78 mg, up to 65 mg, or up to 52 mg, which encompass the claimed dose “30 mg” in Claim 19, thus rendering the claimed dose to be obvious. See MPEP 2144.05.
The method of Zhu et al. differs from the claimed method mainly in that intrathecal (IT) administration, not intracerebroventricular (ICV) administration through a cerebral lateral ventricle, is used for delivering the IDS-β composition into the cerebrospinal fluid (CSF) to a patient with Hunter syndrome.
However, Zhu et al. further teach that the iduronate-2-sulfatase composition of their invention can be administered/delivered directly to the CSF through either intrathecal (IT) route or intracerebroventricular (ICV) route (page 2, left col, para 1). Zhu et al. further demonstrated that the ICV administration of iduronate-2-sulfatase into the left cerebral lateral ventricle in a mammal animal model, by using a catheter system, effectively delivered iduronate-2-sulfatase along with NaCl and polysorbate-20 (pH 6.0) into the deep brain tissues, just like the IT administration did (Example 6, paras. 0384-0386).
Keimei et al. teach a method of treating inborn genetic diseases including lysosomal storage diseases, caused by deficiencies of active enzymes within cells of the central nervous system, comprising a step of either intracerebroventricular or intrathecal administration of a therapeutic protein formulation to the central nervous system of a subject by using an implantable catheter system (abstract, Figs. 1, 4), wherein the lysosomal storage diseases include Hunter’s syndrome caused by deficiency of iduronate-2-sulfatase; and a therapeutic protein for treating Hunter’s syndrome is iduronate-2-sulfatase (page 3/Table 1/the “e.” section, paras 0084/lines 4-6 from bottom, 0077/page 9/left column/line 3 from bottom, 0085/first 3 lines and line 8 from bottom). Keimei et al. also teach that the intracerebroventricular administration delivers the therapeutic protein to fluid-filled cerebral ventricles within the brain, wherein the fluid is a cerebrospinal fluid (CSF) that fills the spaces in the ventricle(s) (paras 0045, 0047/lines 1-7, Fig. 10); wherein the ventricle(s) are(is) the lateral, third and/or fourth ventricles, which are the principle source of CSF (0047, lines 1-6); wherein the implantable catheter system comprises an implantable catheter for withdrawing fluids and introducing therapeutic protein formulation, and an implantable reservoir containing the therapeutic protein formulation to be delivered by the catheter that is fluidly connected to the reservoir (paras 0043, and second half of 0061); wherein the catheter system is surgically inserted, in which the catheter is an intracerebroventricular catheter with its tip/end penetrated through the brain tissue and into cerebral ventricle “1001”, and the reservoir is located under the scalp of the subject for delivering the therapeutic formulation to the cerebrospinal fluid (paras 0062/lines 1-7, 0063/lines 4-6 from bottom, 0058/lines 1-3, Fig. 10 and 2). It is noted that as shown in the Fig. 10 of Keimei et al., the cerebral ventricle “1001” to be administered intracerebroventricularly with therapeutic formulation is a C-shaped cerebral ventricle, thus being a cerebral lateral ventricle, as evidenced by Thorne et al., who teach that that the brain contains two large c-shaped lateral ventricles (“LV”, one on each side of the brain), a single third ventricle (“3V”), and a single fourth ventricle (“4V”) (para 0006/lines 1-7, Fig. 1C and 1D).
It would have been obvious to modify the method of Zhu et al. by replacing the intrathecal (IT) administration of the composition of iduronate-2-sulfatase/I2S (i.e. IDS-β) comprising the sequence of SEQ ID NO:1 with intracerebroventricular (ICV) administration of the IDS-β composition through a cerebral lateral ventricle (e.g. a left lateral ventricle) for treating the subject with a lysosomal storage disease, specifically Hunter syndrome. This is because that the ICV administration is an art-recognized equivalent of the IT administration for the same purpose, and the ICV administration through a cerebral lateral ventricle (e.g. a left lateral ventricle) is as effective as the IT administration for directly delivering the IDS-β therapeutic agent along with NaCl and polysorbate-20 to the CSF in the brain, as supported by Keimei et al. and Zhu et al.
In addition, a catheter system is commonly used in the art for intracerebroventricularly delivering therapeutic agent/iduronate-2-sulfatase to CSF in a lateral ventricle, as supported by Keimei et al. and Zhu et al. Given that the ICV administration through a lateral ventricle allows the therapeutic agent of iduronate-2-sulfatase to be effectively delivered across the blood-brain barrier to reach deep brain tissues, substitution of the intrathecal (IT) administration with the intracerebroventricular (ICV) administration and the therapeutic results of the substitution in the method of Zhu et al. would have been predictable.
Regarding the limitations about the steps 1) and 4) involved with administration with a catheter system as recited in claim 19, Keimei et al. teach applying a catheter system comprising reservoir and a catheter connected to the reservoir for delivering therapeutic agent (iduronate-2-sulfatase) to the cerebrospinal fluid. In addition, Keimei et al. teach surgically inserting an intraventricular catheter system for intraventricular administration of therapeutic agent, in which the reservoir is located under the scalp of the subject and an end of the catheter is located in a cerebral ventricle of the subject, so that a cerebral ventricular inner space is connected, via a catheter inner space, to a reservoir inner space, as indicated above. Given Keimei et al. teach that the inner space of ventricles is filled with cerebrospinal fluid (CSF) (paras 0045, 0047), it would be expected that the connection to the ventricle inner space to the reservoir inner space in the method suggested by Zhu et al. and Keimei et al. would allow CSF to flow from the cerebral ventricle to the reservoir and causing the reservoir to be filled with the CSF. Keimei et al. further teach injecting the therapeutic protein formulation into a reservoir, and allowing the drug/therapeutic protein formulation to flow from the reservoir, via the catheter, to the targeted delivery area, i.e. cerebral ventricle (paras 0099/right col/lines 3-6, 0018/lines 3-4 and 6-9). Thus, the teachings of the cited prior art meet the requirement of the steps 1) and 4) in the claim 19.
Regarding the steps 2) and 3) recited in claim 19, Keimei et al. further teach controlling injection/delivery of the therapeutic protein formulation at a certain rate for providing controlled dosing ranges and preventing toxic side effect of treatment (para 0099, right col, last 6 lines); Zhu et al. and Keimei et al. are silent about specific rates and procedure details recited in the steps 2) and 3). However, it would have been obvious to withdraw about 0.1 to 5 mls of CSF from the reservoir before injecting the therapeutic composition into the reservoir in the method suggested by Zhu et al. and Keimei et al. for intracerebroventricularly administering iduronate-2-sulfatase composition for treating Hunter syndrome, because it is a well-known procedure in the art to withdraw a few milliliters of CSF before injecting a therapeutic composition to cerebrospinal fluid (CSF) for delivering the therapeutic composition into the CSF of lateral ventricle(s). In support, Thorne et al. teach that the most common routes for administering a therapeutic agent composition into the CSF include intracerebroventricular (ICV) and intrathecal (IT) routes, wherein the ICV administration delivers the composition to a lateral ventricle(s) (LV) and it provides a strategy that delivers a variety of agents to wide areas of the CNS due to circulation of CSF within the ventricular and extraventricular compartments (paras 0007/lines 1-12, 0012/lines 1-6, 0079/lines 3-6, Fig. 2). Thorne et al. also teach ICV administration is achieved by implanting a catheter connected to a subcutaneous reservoir that is repeatedly accessible by puncturing through the scalp for drug delivery, and Thorne et al. further teach that generally, a few milliliters of CSF is withdrawn from the reservoir before injecting the therapeutic agent (para 0085). It is noted that “a few milliliters” taught by Thorne et al. renders the claimed range of about 0.1-5 ml to be obvious, because it at least overlaps (if not reads on) with the claimed range.
Regarding the flow rate range “0.1 to 60 ml/min” recited in the steps 2) – 3) of claim 19, this range is very broad. It would have been obvious to withdraw CSF and then inject IDS-β at the claimed flow rate of 0.1 to 60 ml/min in the method suggested by Zhu et al., Keimei et al. and Thorne et al. for treating the patient with Hunter syndrome, because it is well known in the art that the CSF can be withdrawn from and returned (with a therapeutic agent) to the cerebral ventricle at the claimed flow rates for effectively delivering an active agent into the CSF for treating patients. In support, Lad et al. teach a method for treating diseases that affects the CNS through conditioning CSF by removing target/toxic compounds from CSF and/or delivering a therapeutic agent to the CSF of the cerebral ventricle, comprising introducing a catheter system into a cerebral ventricle, withdrawing CSF via the catheter system from the cerebral ventricle and returning the withdrawn CSF to the cerebral ventricle (after the CSF is conditioned or added with a therapeutic agent) (abstract, paras 0027-32, 0134), wherein the CSF is withdrawn and returned at a flow rate in a range of 0.04 ml/min to about 30 ml/min, or about 5 ml/min to about 30 ml/min (para 0033) (NOTE: these flow rate ranges either read on or overlap with the claimed range). Further in support, Thorne et al. teach a flow rate of 40-56 ml over 50 minutes (i.e. 0.8 – 1.12 ml/min that reads on the claimed range) for human subject based on the total volume of CSF (para 0091/lines 1-3); and a rate of 118-280 microliters/min (i.e. 0.118 -0.28 ml/min that reads on the claimed range) for human subject based on the CSF production rates (para 0091/lines 3-8). Examiner notes that a flow rate for withdrawing CSF and introducing therapeutic composition is readily adjustable in the method suggested by the cited prior art for effectively controlling dosing ranges and preventing toxic side effect of treatment, based on specific therapeutic agent and animal conditions. In view of further teachings of Thorne et al. and Lad et al., the claimed rates for withdrawing CSF and introducing pharmaceutical composition would have been obvious to one of ordinary skill in the art.
Regarding the limitations about the clinical outcomes of administering IDS-β recited in claim 19, Zhu et al. further teach: (i) that the administration of IDS-β is highly efficient, clinically desirable, and patient-friendly, and it does not cause adverse effects such as severe immune response, adaptive T cell-mediated immune response, toxicity, and death (paras 0011, 0023, 0133, and 0256); (ii) that the administration of IDS-β reduces cellular vacuolization in neuron/brain cells of the subject and the vacuolization is decreased by more than about 5% up to 100%, compared to a control (a level in pre-treated subject) (para 0248); and (iii) the administration of IDS-β leads to partially or complete amelioration, reducing severity, improvement of neurological impairment, including cognitive impairment (i.e. improving cognitive brain function or learning-memory ability) and ventriculomegaly, in a Hunter Syndrome patient, (para 0246, lines 1-9 and last line). With regard to the decrease in accumulation of heparan sulfate (HS) recited in the claim, Zhu et al. teach that Hunter syndrome is a heritable metabolic disorder resulting from a deficiency of the enzyme iduronate-2-sulfatase (I2S), which causes accumulation of HS because this enzyme plays an important role in the catabolism of HS (para 0243, Table 2). It would be expected that administration of the enzyme in the method suggested by Zhu and other cited prior art would promote the breakdown of heparan sulfate (HS), thus reducing the HS accumulation in the patient. Zhu et al. do not teach HS accumulation is reduced at a level 20% or more. However, the clinical outcome limitations in the claim 19 are directed to what the claimed method does to the subject, not to what the method is (i.e. not to steps of the claimed method). Zhu et al. suggest a method comprising all step limitations recited in the instant claims. It is presumed that methods having substantially the same steps are capable of generating substantially the same clinical outcomes. Thus, the teachings of the cited prior art meet the claimed outcome limitations in the claim 19.
Regarding Claim 27, Zhu et al. teach the subject is a mouse (Example 7, para 0388). The claimed method of treating a mouse would be obvious over the teachings of Zhu et al. in view of the fact that the treatment conditions including IDS-β dosages taught by the cited prior art can be readily modified through routine optimization for treating a mouse subject. See MPEP 2144.05, which summarily states that inventions that mainly depend on the dosages and/or overlapping ranges are rendered obvious. Therefore, the claimed method cannot be considered as being novel just for adjusting dosages of a known drug for treatment.
Regarding Claim 36, Zhu et al. teach a concertation of NaCl, specifically about 154 mM, which read on the claimed NaCl concentration range, as indicated above. Regarding the claimed concentration range for polysorbate 20, Zhu et al. teach that polysorbate 20 has a concentration of approximately 0.005%, as indicated above, and Zhu et al. further teach that 0.005% polysorbate 20 protects the protein therapeutic agent against shacking related stress (para 0342/lines 8-10). If assuming the commonly used unit “gram %ml” (i.e. gram per 100 ml) is used for this concentration, the approximately 0.005% of Zhu et al. is equivalent of about 0.05 mg/ml, reading on the claimed concentration range of about 0.01 to 0.5 mg/ml. Alternatively, it would have been obvious to try the common concentration unit “gram %ml” for preparing the formulation comprising polysorbate 20 at a concentration of about 0.005 g per 100 ml (i.e. about 0.05 mg/ml) in the method suggested by the cited prior art for achieving a desired protection effect, because there are a limited number of units that can be applied to the concentration of about 0.005% taught by Zhu et al. See MPEP 2143 I.E., the rationale “obvious to try” supports a conclusion of obviousness when there is a finite number of identified and predictable solutions in the prior art, and choosing from such a finite number of identified and predictable solutions would have a reasonable expectation of success. Thus, the claim 36 would have been obvious over the combined teachings of the cited prior art.
Regarding Claim 39, it is noted that the brain has only two lateral ventricles (one right lateral ventricle and one left lateral ventricle on each side of the brain), as taught by Thorne et al. It is an obvious design choice to administer the iduronate-2-sulfatase/I2S (i.e. IDS-β) to a single lateral ventricle (a left or right ventricle) or to both lateral ventricles (both left and right ventricles) in the method suggested by Zhu and other cited prior art, because both ways can directly deliver the iduronate-2-sulfatase (I2S) to the cerebrospinal fluid (CSF) so as to treat Hunter syndromes. Furthermore, it is well known in the art to directly deliver a therapeutic agent to both of left and right lateral ventricles for treating lysosomal storage diseases, include Hunter syndrome, as supported by Keimei et al., who further teach directly delivering a therapeutic agent to two lateral ventricles (one left and one right lateral ventricles) at both sides of the brain (see Figs. 4 and 5). Thus, the claim would have been obvious over the teachings of the cited prior art.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Double Patenting
Claims 19, 22, 26-27, 30-31, 35-36 and 39 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-17 of U. S. Patent No. 11052135 in view of Zhu et al. (US 2014/0271598, 2014, of record), as evidenced by Thorne et al. (US 2017/0105927, Apr. 20, 2017, of record). This rejection is maintained.
The claims of the ‘135 patent are directed to a method of treating Hunter Syndrome, comprising a step of administering intracerebroventricularly (ICV administration) to a subject in need of treatment a therapeutically effective dose of an ICV formulation comprising idursulfase-beta (IDS-β); wherein said ICV administration is through an intraventricular catheter system comprising a reservoir and a catheter connected to said reservoir; wherein the method further comprises steps of surgically implanting said intraventricular catheter system, wherein said reservoir is placed between the scalp and the brain of the subject in need of treatment and the end of said catheter is placed inside the ventricle of said subject such that the inner space of said reservoir is connected to the inner space of said ventricle through the inner space of said catheter so that cerebrospinal fluid flows from said ventricle into said reservoir to fill said reservoir; drawing out 0.1-5 ml of cerebrospinal fluid from said reservoir at a flow rate of 0.1-60 ml/minute; injecting 0.1-5 ml of said ICV formulation into said reservoir at a flow rate of 0.1-60 ml/minute; and allowing said ICV formulation of IDS-β to flow from said reservoir through said catheter into said ventricle; wherein said ICV formulation comprises idursulfase-beta (IDS-β) protein at a concentration of approximately 15 mg/ml (reading on the claimed concentration “15 mg/ml” in instant claim 19), Sodium chloride at a concentration of approximately 150 mM (reading on the claimed range in claim 36), polysorbate 20 at a concentration of approximately 0.05 mg/ml (reading on the claimed range in claim 36) and a pH of approximately 6 (reading on the pH in claim 19); wherein said therapeutically effective dose is ranging from approximately 1 mg to approximately 30 mg (encompassing the claimed dose in instant claim 19, thus rendering the claimed dose obvious); wherein said ICV administration is performed once every three weeks or once every month (Note: this renders the claimed interval of 4 weeks to be obvious because it is reasonably suggested by the interval of one month (about 4 weeks) for the reasons indicted above); wherein said ICV administration is performed in combination with at least one additional route of administration of enzyme replacement therapy treatment for Hunter Syndrome; wherein said additional route of administration is intravenous administration, subcutaneous administration, or a combination thereof (reading on the “additional enzyme replacement therapy” in claims 30-31); wherein said intravenous administration is performed once every week, and said subcutaneous administration is performed once every week or twice every week.
The claimed method of the ‘135 patent differs from the instantly claimed method in that the claims of the ‘135 patent are silent whether the idursulfase-beta (IDS-β) has the amino acid sequence of the SEQ ID NO: 1 as recited in the instant 19, and the claims of the ‘135 patent are silent about how many times for idursulfase-beta (IDS-β) to be administered to the subject.
The teachings of Zhu et al. are described above.
It would have been obvious to administer the idursulfase-beta (IDS-β) having the amino acid sequence of the instantly claimed SEQ ID NO: 1 to the subject in the claimed method of ‘135 patent for treating Hunter syndromes, wherein the administration is performed for at least 6 times to the subject, because it is well known in the art that IDS-β (iduronate-2-sulfatase) having the sequence of the instantly claimed SEQ ID NO: 1 with an administration frequency of at least 6 times is effective at treating Hunter syndromes, as supported by Zhu et al.
Regarding the limitations of one or two cerebral lateral ventricles recited in Claims 19, 22, and 39, the claims of the ‘135 patent teach delivery of IDS-β into a cerebral ventricle in the brain through ICV administration. Although the claims of the ‘135 patent do not specifically teach administering to one or two lateral ventricles, it would have been obvious to try administering IDS-β either into a single lateral ventricle (a left or right ventricle) or into both left and right lateral ventricles in the brain of the subject in the method of the ‘135 patent for treating Hinter Syndrome, thus arriving at the claimed method. This is because there are only four cerebral ventricles in the brain of a subject, and two of them are lateral ventricles (one on left side and one on right side of the brain), as evidenced by Thorne et al. (para 0006/lines 1-7, Fig. 1C and 1D, Fig. 2). Thus, intracerebroventricular administration has very limited routes for directly delivering IDS-β into a ventricle(s) in the method of the ‘135 patent. See MPEP 2143 I.E., the rationale “obvious to try” supports a conclusion of obviousness when there is a finite number of identified and predictable solutions in the prior art, and choosing from such a finite number of identified and predictable solutions would have a reasonable expectation of success. Thus, the claimed limitations would have been obvious.
Regarding the limitations about the clinic outcomes recited in claims 19, these limitations are directed to what the claimed method does to a subject with Hunter syndrome, not to what the method is (i.e. not to steps of the claimed method). The method suggested by the claims of the ‘135 patent and Zhu et al. comprises all step limitations recited in the instant claims. It is presumed that methods having substantially the same steps are capable of generating substantially the same outcomes. Furthermore, the administration of IDS-β to patients with Hunter Syndrome indeed is safe, not causing a severe adverse effect (specifically adaptive T cell-mediated immune response, toxicity, or death); and it decreases cellular vacuolization in brain cells; and it improves a brain function or learning-memory ability, as supported by Zhu et al.
Regarding the instant claims 26 and 27, the claims of the ‘135 patent are silent about whether the subject is a non-human mammal or human or a mouse. However, it would have been obvious to apply the claimed method of the ‘135 patent for treating Hunter syndromes in a human subject or a mouse, because Hunter Syndrome is a lysosomal storage disease in human and its treatment is investigated in a mouse model, as supported by Zhu et al.
Therefore, in view of Zhu et al., the method of Claims 19, 22, 26-27, 30-31, 35-36 and 39 of the instant application is deemed obvious over the method of Claims 1-17 of U. S. Patent No. 11052135.
Response to Arguments
Applicant's arguments about the rejection of Claim 23 under 35 USC 112(b) in the response filed on 02/19/2026 (page 7) have been fully considered, but they are moot because the rejection has been withdrawn as indicated above.
Applicant’s arguments about the rejection of Claims 19, 22-23, 26-27, 30-31, 35-36 and 39 under 35 USC 103 over Okuyama et al. in the 02/19/2026 response (pages 8-9) have been fully considered, but they are not persuasive for the following reasons.
First, Applicant’s arguments based on the effects of administering 30 mg IDS-beta in Examples 1-7 of the specification in page 8 of the response are based on the features not recited in the claims, because the base claim 19 specifically limits the dose of the administration to 30 mg, not 30 mg, of IDS-beta. Second, Okuyama et al. expressively teach/suggest a method of treating a patient with Hunter syndrome by administering IDS-beta into lateral ventricle at a dosing regimen, which includes the claimed frequence of once every four weeks for at least 6 times and the claimed dose of 30 mg IDS-beta, which renders the claimed administration frequence and dose to be obvious, as indicated above in the 103 rejection (see details in pages 3-5). With regard to Applicant’s arguments based on the resulting clinical outcomes/characteristics (e.g. decreases in HS accumulation) in page 8 of the response, they are not persuasive because the teachings of Okuyama et al. meet the limitations about the clinical outcomes recited in the claim 19, for the reasons indicated above in the 103 rejection (see details in pages 5-6). With regard to Applicant’s arguments based on Thorne et al. in last para of page 8 of the response, these arguments are moot because the reference of Thorne et al. is cited as an evidence, not the prior art, in the 103 rejection. In response to Applicant’s arguments based on Figure 4 in the specification of the instant application in the response (page 9), it is a common practice in the art to carry out the repeated administration of IDS-beta for treating Hunter syndrome and Applicant’s arguments are not persuasive for the reasons of record (see page 25 of the previous office action dated 11/19/2025).
Overall, the claimed method of administering at the claimed dosing regimen IDS-β having the sequence of SEQ ID NO: 1 has no novelty in view of the teachings of Okuyama et al.
Applicant’s arguments about the rejection of Claims 19, 22-23, 26-27, 30-31, 35-36 and 39 under 35 USC 103 over Zhu et al. in view of Keimei et al., Thorne et al., and Lad et al. in the 02/19/2026 response (pages 9-11) have been fully considered, but they are not persuasive for the following reasons.
In response to Applicant’s arguments based on repeated administration of IDS-beta and its resulting clinical outcomes in page 9/last para of the response, Examiner notes that it is a common practice in the art to repeatedly administrate IDS-beta for treating Hunter syndrome, as indicated above; and Zhu et al. teach/suggest a method for treating Hunter syndrome by administering a pharmaceutical composition comprising IDS-b, at a dose range comprising the claimed 30 mg for at least 6 times at an interval of about 4 weeks to the patient, as indicated in the 103 rejection above. Furthermore, the resulting clinical outcomes (effect of the administration) recited in the claim 19 are obvious over the combined teachings of Zhu et al. and other cited prior art for the reasons indicated in the 103 rejection above.
In response to Applicant’s remaining arguments about Zhu et al. in pages 9 and 10 of the response, Examiner notes that Zhu et al. do not teach away from the claimed method. Rather, Zhu et al. expressively teach that the stable formulations of iduronate-2-sulfatase according to their invention can be delivered into the CNS and CSF either by intrathecal (IT) administration or by intracerebroventricular (ICV) administration (page 2, left col, para 1). Zhu et al. further demonstrate that the ICV administration of iduronate-2-sulfatase (IDS-b) into cerebral lateral ventricle in a mammal animal leads to widely distributing iduronate-2-sulfatase throughout the brain tissues, as the IT administration did (Example 6, paras. 0384-0386; Fig. 47 and para 0082). These teachings from Zhu clearly indicate that the ICV administration is an effective route for delivering iduronate-2-sulfatase into the CNS and CSF. With regard to Fig. 62 A-C cited by Applicant, this figure clearly shows that the ICV administration effectively delivered the agent into both the spinal cord and the brain; and the ICV administration is superior to the IT administration because the agent is more widely distributed in the brain/deep brain regions compared to the IT administration, in contrary to Applicant’s arguments about better distribution from the IT administration. With regard to the paragraph 0211 cited by Applicant, Zhu et al. in this para teach delivering replacement enzymes to “various layers or regions of the brain, including deep brain regions” for treating patients, which indicates that targeting the enzyme agent into the brain and deep brain regions is important for treating Hunter syndrome. Given the agent can be effectively delivered by the ICV administration to both the spinal cord and the brain/deep brain regions (as shown by Fig. 62), the paragraph 0211 does not teach away from using the ICV administration. Furthermore, Applicant’s arguments based on “the importance of the enzyme distribution throughout the entire CSF region” in page 10 of the response is misleading. There is no disclosure in Zhu et al. to require the enzyme to be distributed throughout the entire CSF region for the treatment. Further, the IT administration can only deliver the agent to a small portion of the CSF in the brain, not to the entire CSF region of the CNS, as shown by Fig. 62. As such, the IT administration does not lead to the enzyme distribution throughout the entire region of the CSF, as Applicant argued.
In response to Applicant’s arguments about Keimei, Lad, and Thorn in pages 10-11 of the response, Examiner notes that the ICV administration is an art-recognized equivalent of the IT administration for delivering the IDS-β therapeutic agent, as further supported by Keimei et al. It would have been obvious to modify the method of Zhu by adopting the teachings of Keimei, Lad, and Thorn, thus arriving at the claimed method, for the reasons indicated in the 103 rejection above.
Overall, the conclusion of the obviousness of the instantly claimed method of ICV administration of IDS-β having the sequence of SEQ ID NO: 1 has been established over the combined teachings of Zhu et al., Keimei et al., Thorne et al., and Lad et al. for all the reasons indicated above.
Applicant’s arguments about the double patenting rejection over claims of U. S. Patent No. 11052135 in view of Zhu et al. in the 02/19/2026 response (page 11) have been fully considered, but they are not persuasive. Applicant’s arguments are based on those arguments previously presented for the 103 rejections. Since Applicant’s arguments for the 103 rejections are found not persuasive (for the reasons indicated above), the double patenting rejection is maintained in this office action.
Conclusion
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 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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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